Concomitant chemoradiation therapy in the Radiation Oncology Unit: can it make a difference?

Introduction

Squamous cell head and neck cancer (SCHNC) is a group of malignancies that involve the oral cavity, pharynx, hypopharynx, larynx, nasal cavity, and salivary glands. The incidence is increasing, with 660,000 new cases in 2020 and a predicted 30% increase annually by 2030 (1). Standard treatment of unresectable locally advanced SCHNC is concurrent chemo-radiation therapy and in some instances induction chemotherapy to concomitant chemoradiation (2,3). Radiation therapy is delivered 5 days a week over 6 to 7 weeks. The standard fractionation schedule accommodates the weekend breaks which are considered to compensate for tumour repopulation during the non-treatment days. The total time of treatment without further interruption is 49 days. To achieve higher overall survival rates and locoregional control, the European Organization for Research and Treatment of Cancer (EORTC), Radiation Therapy Oncology Group (RTOG), and the European Society of Medical Oncology (ESMO) recommended concomitant chemoradiation therapy (cCRT). In most of cases, the chemotherapy regimen consists of intravenous cisplatin 100 mg/m² on days 1, 22, 43, or weekly 40 mg/m² cisplatin (4-7). In patients with contraindications for cisplatin, concomitant cetuximab can be an alternative treatment (400 mg/m² on initial dose day −8 followed by 250 mg/m² weekly concurrent) (8).

Several studies demonstrate a low adherence to treatment when concomitant chemoradiotherapy is administered with a range of 30–60% of head and neck cancer (HNC) patients missing at least one cycle of weekly cisplatin chemotherapy. Unplanned interruption of the treatment can be associated with several factors that lead to a negative impact on local control (LC) and overall survival rate (9,10). The main factors related to treatment breaks are public holidays, machine malfunction, patient compliance, socioeconomic factors, toxicities, and other therapy patient-related factors. Among the latter, even a delay in the admission-to-chemotherapy time, the time between the patient’s arrival in the Oncology Unit (OU) and the beginning of planned chemotherapy, can negatively affect patient care (11-13). Overall, these factors are associated with suboptimal use of resources and higher costs, increased length of stay with high risk of nosocomial infections, and patient dissatisfaction (14,15).

In many countries, chemotherapy administration is not common for radiation oncologists (ROs). Our study was conducted in Italy, where ROs are licensed to prescribe and administer chemotherapy. However, in some Italian regions it is forbidden to administer chemotherapy in radiotherapy units. This is an inexplicable misinterpretation of the national law. A partial exemption allows the administration of chemotherapy in university hospitals. This issue is the starting point that led us to investigate how different managements in the administration of cCRT may impact the quality of treatments.

The aim of our multicentric study is to evaluate how administering cCRT in the same medical unit can impact on the total time treatment delivery. This is a stewardship study, and clinical outcomes are out of our study aims. We present this article in accordance with the STROBE reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-23-35/rc).

Methods

We retrospectively enrolled all patients submitted to definitive cCRT for locally advanced SCHNC from January 2022 to December 2022. Patients came from university and non-university teaching hospitals and inclusion criteria were: age >18 years, biopsy proving SCHNC, and availability of complete clinical and radiological data. According to the unit where chemotherapy treatments were administered, patients were allocated into two groups: Group A, patients who were submitted to cCRT in the same clinical unit [Radiation Oncology Unit (ROU), university hospital]; in Group B, patients received cCRT in two different clinical unit: chemotherapy in the OU and radiation therapy in the ROU (non-university teaching hospital). Patients surgically resected, in palliative settings or unfit for chemotherapy were excluded. Using Common Terminology Criteria for Adverse Events (CTCAE), toxicity grades were evaluated. Clinical and treatment data were collected in a digital archive.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethical approval was waived by the ethics committee of Messina because the study was conducted following administrative methodology (“record and verify” in daily clinical practice). Because of the retrospective nature of the research, the requirement for informed consent was waived.

Statistical analysis

Descriptive parameters were reported as mean ± standard deviation, median, and range. The association between interruption rate and time of the treatment corresponding curves was estimated using the Cox regression models. Data were analysed using GraphPad software (GraphPad Prism version 6.0).

Results

Thirty-three patients (5 female, 28 male) with a median age of 62 years [range, 33–83 years; interquartile range (IQR) ±11.25 years] were enrolled. The most frequent site of primary disease was oral cavity and nasopharynx followed by the larynx and oropharynx. The subsites are summarized in Table 1; 48.5% (16/33) received chemotherapy in the ROU (Group A), 51.5% (17/33) in the OU (Group B).

Radiotherapy treatment

All patients received radiation therapy with a median delivered dose of 66 Gy (range, 44–76 Gy; IQR ±4 Gy). Of them, 15 received a sequential boost, and 18 a simultaneous integrated boost (SIB).

Twenty-six patients (26/33; 13 Group A and 7 Group B) completed cCRT treatment in the expected time (≤49 days); 2 Group A patients and 4 Group B patients interrupted cCRT and completed radiation therapy beyond 49 days; 7 patients did not reach the prescription dose (1 from Group A and 6 from Group B, respectively).

Chemotherapy regimen

Twenty-five patients (25/33; 10 Group A and 15 Group B) underwent cCRT with weekly cisplatin regimen chemotherapy; 18 of them completed treatment (12 from Group A and 6 from Group B); 7 of them interrupted treatment (1 from Group A and 6 from Group B).

Eight patients (8/33) received a platin-based induction chemotherapy regimen and completed chemoradiation treatment: in 5 patients belonging to Group A cisplatin 100 mg q21 was administered; 1 from Group B received weekly carboplatin; in 2 cases the chemotherapy regimen was not specified.

Toxicities

Among patients who completed treatment, 1 patient showed hearing loss (Grade 2), 1 dysphagia (Grade 2) and mucositis (Grade 2), and 1 trismus and mycosis (Grade 2).

Out of 7 patients who broke treatment, 1 stopped at 44 Gy (out of 66 Gy scheduled) due to cutaneous manifestations (Grade 3); 6 patients interrupted cCRT for their own reasons (difficulties related to moving from the ROU to the OU and difficulties related to interaction with doctors of different units) and 2 of them showed mucositis (Grade 2).

Patients’ characteristics are summarized in Table 1.

Discussion

A significant statistical difference was observed between patients of Group A and Group B in our retrospective study. Figure 1 shows the interruption rate in Group A and Group B. It is important to declare the limitations of our study: the number of patients included was limited and came from university hospitals and non-university teaching hospitals. This is a retrospective study focused on administering of cCRT in patients with locally advanced stage, therefore no sub-analysis of pathological-stage and field-wideness (volumes) was performed.

Figure 1 Interruption rate in Group A and Group B. Group A, patients received chemotherapy in a Radiation Oncology Unit; Group B, patients received chemotherapy in an Oncology Unit.

The management of HNC is complex and requires a multidisciplinary approach.

In early-stage cancer, surgery, and radiotherapy provide similar locoregional control and survival outcomes (16) except in nasopharyngeal carcinoma where surgery is excluded, and radical radiotherapy represents the first-line treatment (17,18).

In locally advanced HNC a combined approach is required. Chemoradiation therapy consists of the administration of cisplatin weekly or every three weeks in association with radiation therapy performed in 30–35 days.

The length of radiation therapy and in combination with chemotherapy can increase toxicities and the interruption of treatment.

Only for unresectable or recurrent HNCs, stereotactic body radiation therapy (SBRT) in 5 fractions, can be considered (19,20).

Among toxicities, mucositis is mostly related to the treatment gap due to pain and burning sensation (21).

Trotti et al. reported an incidence rate of mucositis of 97% during classic RT, 100% during altered fractionation, and 89% during chemoradiation therapy (22).

The severity of symptoms is related to the length of the delayed treatment (23,24).

Prolongation of the treatment is associated with a decrease in LC and an adverse response to treatment, due to a reduction in biological effectiveness (25,26).

Robertson et al. reported a reduction of LC of 0.68% and 3.5% per day after a 1- and 5-day gap in the treatment, respectively. The authors suggested treating at the weekend or giving two fractions on the day after the 1-day gap rather than extending the treatment time or modifying the dose (27).

The RTOG in two phase III studies (RTOG protocols 79-13 and 79-15) showed an LC rate of 27% for those patients who did not have a prolonged treatment time and 13% for patients with a treatment time prolonged by 14 days or more (28).

Taylor et al. found that the total dose must be increased by about 1 Gy for each extra day added, in order to obtain a similar tumor control (29).

Few studies investigated in detail the causes of treatment interruptions. The main causes reported were public holidays, machine malfunction, patient compliance, socioeconomic, time of treatment, and therapy-related factors (30-34).

Kwong et al. found that interruptions occurring at the beginning of treatment did not significantly affect prognosis (31).

Treatment initiation time is crucial.

Wyatt et al. reported that each additional week of time between diagnosis and the beginning of treatment for HNC patients decreases an LC rate of 1% (11). Jensen et al. reported that after waiting 28 days, 62% of patients had a 46% increase in tumour volume and 20% had metastases to lymph nodes (35); Shaikh et al. evaluated the time between surgery and postoperative radiotherapy and found that this interval is optimal when it is 6 weeks or less (36-38).

A negative impact on patient care can be related to a delay in the time of admission to chemotherapy when patients arrive at the OU. Early chemotherapy onset was observed in patients with pre-admission and already having laboratory results compared to those who were directly admitted from home. Man and Gupta formed a team participating in ASCO’s Quality Training Program (ASCO’s QTP) with the aim of improving time to chemotherapy admission, leading to a reduction of stay and improvement in patient experiences and suggested the use of classic quality improvement (QI) tools to assess the causes of delay (12,13).

Therefore, here we have evaluated if administering cCRT in the same medical unit can impact the quality of treatment.

In our series, patients were divided into two groups according to the medical unit where chemotherapy was administered and the interruption rates were analyzed. When patients received cCRT in ROUs a lower interruption rate (P<0.001) was observed.

These results may be related to the reduction of time at the beginning of chemotherapy and to a better organization of nursing and physician staff in the administration of cCRT, suggesting that cCRT should be administered in the same medical unit in order to avoid treatment interruptions.

Conclusions

Taking into consideration the limitations of the small patient sample, our analysis highlights how performing cCRT in the same medical unit reduces unplanned interruption improving the quality of treatment. Therefore, it is hoped that every RO should be qualified to administer chemotherapy to reduce patient discomfort and improve treatment adherence. The present study reports original observations due to the lack of literature on this issue (“concomitant administration of chemoradiotherapy in the same unit with respect to two different units”).

Acknowledgments

We are expressing our deepest gratitude and appreciation for the assistance and support received throughout the completion of this research paper. We want to take this opportunity to acknowledge the contributions of the individuals and institutions who have played a significant role in successfully completing this research project. We want to express our heartfelt thanks to our peers and colleagues for their constructive feedback and wonderful collaboration, which enriched the intellectual discourse of this research project. We would also like to extend our sincere gratitude to Ms. Susan Remick for the English editing work of the paper. Her job was crucial to complete our research successfully. We acknowledge the editorial team’s and reviewers’ contributions, which strengthened the clarity and consistency of this research paper. Once again, we are grateful to all those who have contributed immensely to our academic journey.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-23-35/rc

Data Sharing Statement: Available at https://tro.amegroups.com/article/view/10.21037/tro-23-35/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-23-35/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Ethical approval was waived by the ethics committee of Messina because the study was conducted following administrative methodology (“record and verify” in daily clinical practice). Because of the retrospective nature of the research, the requirement for informed consent was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 2021;71:209-49. [Crossref] [PubMed]
2. Pergolizzi S, Santacaterina A, Adamo B, et al. Induction chemotherapy with paclitaxel and cisplatin to concurrent radiotherapy and weekly paclitaxel in the treatment of loco-regionally advanced, stage IV (M0), head and neck squamous cell carcinoma. Mature results of a prospective study. Radiat Oncol 2011;6:162. [Crossref] [PubMed]
3. Iatì G, Parisi S, Santacaterina A, et al. Simultaneous Integrated Boost Radiotherapy in Unresectable Stage IV (M0) Head and Neck Squamous Cell Cancer Patients: Daily Clinical Practice. Rep Pract Oncol Radiother 2020;25:399-404. [Crossref] [PubMed]
4. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945-52. [Crossref] [PubMed]
5. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937-44. [Crossref] [PubMed]
6. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005;27:843-50. [Crossref] [PubMed]
7. Grégoire V, Lefebvre JL, Licitra L, et al. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010;21:v184-v186. [Crossref] [PubMed]
8. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010;11:21-8. Erratum in Lancet Oncol 2010;11:14. [Crossref] [PubMed]
9. Naghavi AO, Echevarria MI, Strom TJ, et al. Treatment delays, race, and outcomes in head and neck cancer. Cancer Epidemiol 2016;45:18-25. [Crossref] [PubMed]
10. Pujari L, Padhi S, Meher P, et al. An audit and analysis of different causes of defaults in patients receiving radiation for head and neck cancers: A tertiary regional cancer center experience. Indian J Cancer 2017;54:31-4. [Crossref] [PubMed]
11. Wyatt RM, Beddoe AH, Dale RG. The effects of delays in radiotherapy treatment on tumour control. Phys Med Biol 2003;48:139-55. [Crossref] [PubMed]
12. Man L, Sen J, Giordano J, et al. Multidisciplinary Effort to Decrease Time From Admission to Chemotherapy on an Inpatient Oncology Unit. J Oncol Pract 2019;15:e728-e732. [Crossref] [PubMed]
13. Gupta A, Li J, Tawfik B, et al. Reducing Wait Time Between Admission and Chemotherapy Initiation. J Oncol Pract 2018;14:e316-e323. [Crossref] [PubMed]
14. Accordino MK, Wright JD, Vasan S, et al. Factors and Costs Associated With Delay in Treatment Initiation and Prolonged Length of Stay With Inpatient EPOCH Chemotherapy in Patients With Hematologic Malignancies. Cancer Invest 2017;35:202-14. [Crossref] [PubMed]
15. Lis CG, Rodeghier M, Gupta D. Distribution and determinants of patient satisfaction in oncology: A review of the literature. Patient Prefer Adherence 2009;3:287-304. [PubMed]
16. Chow LQM. Head and Neck Cancer. N Engl J Med 2020;382:60-72. [Crossref] [PubMed]
17. Pfister DG, Spencer S, Adelstein D, et al. Head and Neck Cancers, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2020;18:873-98. [Crossref] [PubMed]
18. Kwong DL, Nicholls J, Wei WI, et al. The time course of histologic remission after treatment of patients with nasopharyngeal carcinoma. Cancer 1999;85:1446-53. [Crossref] [PubMed]
19. Stanisce L, Koshkareva Y, Xu Q, et al. Stereotactic Body Radiotherapy Treatment for Recurrent, Previously Irradiated Head and Neck Cancer. Technol Cancer Res Treat 2018;17:1533033818780086. [Crossref] [PubMed]
20. Pontoriero A, Iatì G, Conti A, et al. Treatment of periocular basal cell carcinoma using an advanced stereotactic device. Anticancer Res 2014;34:873-5. [PubMed]
21. Siddiqui F, Movsas B. Management of Radiation Toxicity in Head and Neck Cancers. Semin Radiat Oncol 2017;27:340-9. [Crossref] [PubMed]
22. Trotti A, Bellm LA, Epstein JB, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol 2003;66:253-62. [Crossref] [PubMed]
23. Yao JJ, Jin YN, Wang SY, et al. The detrimental effects of radiotherapy interruption on local control after concurrent chemoradiotherapy for advanced T-stage nasopharyngeal carcinoma: an observational, prospective analysis. BMC Cancer 2018;18:740. [Crossref] [PubMed]
24. Chen M, Jiang GL, Fu XL, et al. The impact of overall treatment time on outcomes in radiation therapy for non-small cell lung cancer. Lung Cancer 2000;28:11-9. [Crossref] [PubMed]
25. Kawahara D, Nakano H, Saito A, et al. Dose compensation based on biological effectiveness due to interruption time for photon radiation therapy. Br J Radiol 2020;93:20200125. [Crossref] [PubMed]
26. ELKIND MM. SUTTON H. Radiation response of mammalian cells grown in culture. 1. Repair of X-ray damage in surviving Chinese hamster cells. Radiat Res 1960;13:556-93. [Crossref] [PubMed]
27. Robertson C, Robertson AG, Hendry JH, et al. Similar decreases in local tumor control are calculated for treatment protraction and for interruptions in the radiotherapy of carcinoma of the larynx in four centers. Int J Radiat Oncol Biol Phys 1998;40:319-29. [Crossref] [PubMed]
28. Pajak TF, Laramore GE, Marcial VA, et al. Elapsed treatment days--a critical item for radiotherapy quality control review in head and neck trials: RTOG report. Int J Radiat Oncol Biol Phys 1991;20:13-20. [Crossref] [PubMed]
29. Taylor JM, Withers HR, Mendenhall WM. Dose-time considerations of head and neck squamous cell carcinomas treated with irradiation. Radiother Oncol 1990;17:95-102. [Crossref] [PubMed]
30. Maciá I. Compliance to the prescribed overall treatment time (OTT) of curative radiotherapy in normal clinical practice and impact on treatment duration of counteracting short interruptions by treating patients on Saturdays. Clin Transl Oncol 2009;11:302-11. [Crossref] [PubMed]
31. Kwong DL, Sham JS, Chua DT, et al. The effect of interruptions and prolonged treatment time in radiotherapy for nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 1997;39:703-10. [Crossref] [PubMed]
32. Barton MB, Keane TJ, Gadalla T, et al. The effect of treatment time and treatment interruption on tumour control following radical radiotherapy of laryngeal cancer. Radiother Oncol 1992;23:137-43. [Crossref] [PubMed]
33. Alden ME, O'Reilly RC, Topham A, et al. Elapsed radiation therapy treatment time as a predictor of survival in patients with advanced head and neck cancer who receive chemotherapy and radiation therapy. Radiology 1996;201:675-80. [Crossref] [PubMed]
34. James ND, Williams MV, Summers ET, et al. The management of interruptions to radiotherapy in head and neck cancer: an audit of the effectiveness of national guidelines. Clin Oncol (R Coll Radiol) 2008;20:599-605. [Crossref] [PubMed]
35. Jensen AR, Nellemann HM, Overgaard J. Tumor progression in waiting time for radiotherapy in head and neck cancer. Radiother Oncol 2007;84:5-10. [Crossref] [PubMed]
36. Shaikh T, Handorf EA, Murphy CT, et al. The Impact of Radiation Treatment Time on Survival in Patients With Head and Neck Cancer. Int J Radiat Oncol Biol Phys 2016;96:967-75. [Crossref] [PubMed]
37. Harris JP, Chen MM, Orosco RK, et al. Association of Survival With Shorter Time to Radiation Therapy After Surgery for US Patients With Head and Neck Cancer. JAMA Otolaryngol Head Neck Surg 2018;144:349-59. [Crossref] [PubMed]
38. Huang J, Barbera L, Brouwers M, et al. Does delay in starting treatment affect the outcomes of radiotherapy? A systematic review. J Clin Oncol 2003;21:555-63. [Crossref] [PubMed]