Although head and neck cancer accounts for a relatively small proportion of all new cancer diagnosis in the United States, the treatment frequently warrants multi-disciplinary care requiring complex coordination [1]. Given that the addition of cytotoxic chemotherapy to radiation has been shown to improve overall survival and local-regional control in both the definitive and post-operative settings for select head and neck cancer patients with adverse risk features, the use of this multi-modality approach is common [2,3]. When delivered concurrently with radiation, chemotherapy is generally intended to serve as a radio-sensitizer, potentiating the cytotoxic effects of radiation on proliferating tumor cells [4]. While most guidelines for concurrent chemoradiation recommend initiating concurrent chemotherapy on day 1 of radiation (with the administration of chemotherapy preceding radiation), the actual clinical practice may vary in the timing and sequencing of these treatments [5]. This is largely because coordination can be challenging from a logisitical and social standpoint, leading to deviations from the standard. While the reasons for deviations are multi-faceted and speculative, we recently showed, in an analysis of practice patterns focusing on variations in the timing of chemotherapy relative to radiation in patients treated with concurrent chemoradiation for head and neck cancer, that non-compliance to recommendations are common [6].

Indeed, the most startling aspect of the real-world findings was the considerable amount of variability that was observed in the sequencing of radiation with chemotherapy for patients treated by concurrent chemoradiation for head and neck cancer [6]. Although all patients were treated with the paradigm of concurrent chemoradiation, it was demonstrated that significant inconsistencies existed in the timing of how these modalities were practically delivered. For instance, nearly a third of all patients ostensibly treated by concurrent chemoradiation actually had their radiation and chemotherapy delivered on different days. Even for patients who had same-day delivery at the start of treatment, the sequencing of radiation and chemotherapy during a single day was not consistent. For instance, radiation preceded chemotherapy in nearly 10% of cases. While the implications of these findings with respect to outcome are uncertain, they are worth discussing, especially since platinum-based agents are generally given to optimize the effects of radiation.

When used concurrently with radiation, platinum-based agents act as radiosensitizers, increasing damage to malignant nuclear DNA to enhance the anti-neoplastic capability of radiation. The mechanisms by which this radio-sensitization occurs remain controversial, although one leading theory involves cisplatin's ability to inhibit sublethal damage repair in irradiated tumor cells [7]. From a radiobiological standpoint, cisplatin forms intra-strand and inter-strand DNA cross-links that stress the DNA structure and inhibit non-homologous end joining repair of ionizing radiation damage [4]. In addition, the sublethal damage disrupts a variety of signal transduction pathways, including cell cycle control, apoptosis, and production of growth factors [8].

Preclinical studies analyzing the pharmacokinetics of cisplatin have suggested that the synergistic capabilities diminish the farther apart the modalities are delivered [9-12]. In a seminal series of culture experiments using human keratinocytes, Lagrange et al. modeled the effect of radiation on tumor killing by analyzing cell survival as a function of the different times of irradiation within a given drug sequence [11]. The investigators essentially demonstrated that the shorter the time period between cisplatin exposure and the delivery of radiation resulted in the optimal tumoricidal effect. These findings were consistent with those of Gorodetsky et al. who showed in a murine model that the supra-additive effect of cisplatin and radiation could only be achieved when the drug was administered before or shortly after radiation [12]. Notably these researchers showed significantly decreased efficacy when the chemotherapy and radiation was spaced at periods more than 2 hours apart. They proposed that these findings could be related to alteration of the cellular oxygenation, cross resistance, or redistribution in cell cycle.

Marcu et al. similarly suggested from an in vitro study that a shorter time sequence between cisplatin and concurrent radiation led to improved tumor control [13]. Schwachofer et al. also confirmed that the beneficial effect of cisplatin as a radiosensitizer may not hold if there is a time gap of greater than 24 hours between cisplatin and radiation [7]. Indeed, Kallman et al. also showed in murine squamous cell carcinoma models that the delivery of cisplatin timed immediately prior to each fraction versus given as a bolus at the beginning of the radiation course enhanced tumor killing which strongly demonstrated again that the radio-sensitizing effect was timing dependent [14]. For example, it was suggested that cisplatin when administered daily along with radiation led to a 35% improvement of tumor control as compared to a regimen of weekly doses of cisplatin with daily radiation.

To determine the optimal time for radiation delivery in the setting of chemoradiation, Rajkumar et al. prospectively measured the plasma concentration levels of patients receiving cisplatin as either a 40 mg/m2 (over 1 hour) or 100 mg/m2 infusion (over 3 hours) and showed that the levels of cisplatin concentration declined precipitously after the end of infusion in both groups [15]. As early as 30 minutes, the total cisplatin geometric mean concentration was diluted to 59% and 61% of its peak value at the completion of infusion over 1- and 3-hours, respectively. After 2 hours, the mean concentration was approximately 25% for both groups; and by 24 hours, only a fraction of the peak concentration remained. The investigators thus concluded that the most advantageous time to administer radiation, if it is not possible immediately at the end of infusion, would be within 30 minutes.

More recent data has suggested that cisplatin-based chemoradiation leads to immunological responses which may contribute to cytotoxic tumor killing [16-21]. For instance, Gelbard et al. irradiated several squamous cell carcinoma of the head and neck cell lines with in the presence of cisplatin-based chemotherapy at sub-lethal doses to investigate the combined effect on cytotoxic T-lymphocytye mediated tumor killing [16]. The investigators showed that in all 3 tumor cell lines tested, enhanced cytotoxic T-lymphocyte activity was observed when both modalities (chemotherapy and radiation) were combined as compared with target cells exposed to either modality separately. Additionally, the combination treatment regimen led to a 50% reduction in Bcl-2 expression, whereas single modality treatment had little bearing on the expression of this anti-apoptotic gene. Jung et al. similarly demonstrated the potential of irradiation and cisplatin as a chemoradiation regimen to augment the effects of natural killer immune cells in head and neck squamous cell carcinoma [17]. Moreover, monocytic myeloid-derived suppressor cells, which have been implicated as key players in inhibiting anti-tumor immune responses and tumor progression, can be affected by cisplatin [18]. Indeed, numerous other studies have shown that both cisplatin and radiation, as separate modalities, alter tumor immunity [16-21].

Although these preclinical and pharmacokinetic studies in aggregate have strongly supported the administration of radiation shortly after completion of chemotherapy for patients undergoing concurrent chemoradiation, findings from the literature show that adherence to this practice for head and neck cancer patients is lacking [6]. While the underlying reasons are speculative, the logistical challenges associated with the coordination of chemotherapy and radiation have been well documented [22]. These include the resource intensive nature of radiation simulation, treatment planning, and quality assurance, all of which have been shown to potentially delay the process. The availability of chemotherapy infusion chairs, as well as referrals to ancillary services such as dental oncology, swallow therapy, and nutrition, can also complicate scheduling. Lastly, insurance issues can often impede coordination as it is common for authorization to be obtained for one modality before another.

The clinical implications of our findings, while provocative, are uncertain. While it is speculative to propose that timing considerations may potentially compromise cancer control and portend worse outcomes, there is a relative lack of literature addressing this topic. Steber et al. analyzed outcomes among 131 patients treated by concurrent chemoradiation for head and neck cancer based on the timing in which chemotherapy or RT were initiated: chemotherapy first, same day start, within 24 h, or start on Monday/Tuesday/Wednesday [5]. Consistent with pre-clinical data, the investigators showed that starting chemotherapy prior to radiation significantly improved 3-year local-regional control (91% versus 78%). However, clinical outcomes were not different when stratifying by the other variabilities in the timing of initiating chemotherapy or radiation.

Regardless of the clinical repercussions, it must be recognized that real-world practice patterns often differ from the hypothetical standard of how concurrent chemoradiation should optimally be delivered. This highlights the importance of continued quality improvement efforts. From our perspective, this starts with promoting awareness for both patients and providers. For example, findings showing that non-English speaking patients and those from minority backgrounds are more likely to receive treatment that deviates from aspirational standards point to the influence of social determinants of health and the need for targeted initiatives for at-risk populations [6]. This is especially critical given the mounting body of literature suggesting that minority patients with cancer are often under-treated and/or undergo non-guideline-based care [23-25]. Clealy, improvements focusing on health equity and improved access are needed.

In conclusion, substantial deviations were noted in how cisplatin-based concurrent chemoradiation is delivered on a practical, real-world basis for head and neck cancer. From a biological standpoint, these variations are of concern, as pre-clinical studies clearly show that asynchronous delivery of cisplatin and radiation may mitigate the cytotoxic effects of this dual-modality regimen. Quality improvement initiatives focused on improving care coordination and standardizing the delivery of chemoradiation with respect to the timing of the two modalities should be considered. The clinical repercussions of the variations in timing with respect to chemoradiation delivery also deserve further investigation.

The authors indicate no disclosure of potential conflicts of interest.

No sources of funding are acknowledged.