Abstract
Background/Aim: Hypofractionated accelerated radiotherapy (HypoAR) is widely applied for the treatment of early laryngeal cancer. Its role in locally advanced head-neck cancer (LA-HNC) is unexplored. Patients and Methods: We present results of a prospective trial on 124 patients with LA-HNC, treated with radio-chemotherapy with three different HypoAR fractionations (3.5 Gy/day × 14-15 fractions, 2.7 Gy/day × 20-21 fractions, and 2.5 Gy/day × 21-22 fractions). Results: Protraction of the overall treatment time due to oropharyngeal mucositis was enforced in 18/57 laryngeal, 6/19 nasopharyngeal, and 15/48 cancer patients with other tumors. Regarding late toxicities, laryngeal edema grade 3 was noted in 5/57 patients with laryngeal cancer, while severe dysphagia was noted in 4/124 and tracheoesophageal fistula formation in 1/124 patients. The complete response rates obtained were 73%, 84%, and 67% in patients with laryngeal, nasopharyngeal, and other tumors, respectively. The 3-year locoregional progression-free survival was 58%, 73%, and 55%, respectively. Conclusion: HypoAR chemoradiotherapy is feasible, with acceptable early and late radiotherapy toxicities, response rates and LPFS.
The justified, to a certain point, phobia spread over the 1980s and 1990s regarding the severity of late complications from hypofractionation, promoted the switch of clinical trials towards hyperfractionated regimens. Hypofractionation was reduced to a clinical tool for overloaded radiotherapy departments or was used as a research tool by few heretics. In his ‘lessons from complications’ paper, G.H. Fletcher appeared convinced that hypofractionation produces unacceptable late toxicities in breast cancer (1). However, the whole breast’s dose in the image case presented in the article was equal to a normalized biological total dose of 60Gy (5 fractions of 670 cGy). This dose would have produced similarly poor cosmetic results even if given with conventional fractionation. Today, hypofractionated and accelerated radiotherapy (HypoAR) is the standard of care for breast cancer patients (2, 3).
The reconsideration of hypofractionation became feasible due to the technological advances in radiotherapy and, most importantly, the optimized calculation of the biological radiation dose (according to the linear-quadratic model formulas). Moreover, radiobiological analysis of large clinical data dissolved the long-lasting misconception that all tumors have a high α/β-value, challenging the supremacy of small doses per fraction. Today, HypoAR has gained the trust of Radiation Oncologists worldwide for the treatment of breast, prostate, and rectal cancer (2-6). The use of Stereotactic Body Radiotherapy SBRT, applying super-hypofractionated regimens, is gradually increasing, as the publications of favorable experiences are rapidly increasing (7).
Regarding head-neck cancer, HypoAR is considered the standard of care for early laryngeal cancer (8). HypoAR is more effective than conventional radiotherapy (ConvRT) or even surgery for early laryngeal carcinomas (9). However, the overall world experience on HypoAR in locally advanced head-neck cancer (LA-HNC) is limited. Shuryak, Hall, and Brenner have recently suggested that optimized HypoAR can be better tolerated and effective (10). The optimal regimen suggested by the authors for patients with early and LA-HNC, is 18 daily fractions of 3 Gy (delivered in 24 days), while a possible 19th fraction would increase local control rates to 52.7% vs. 35% expected after ConvRT (delivered in 48 days). The normalized total dose (NTD) (without time correction) for early and late toxicities (α/β=10 Gy and 4 Gy, respectively), of the 19-fraction regimen, is estimated at 61.75 Gy and 66.5 Gy, respectively.
Due to the continuously increasing number of patients demanding radiotherapy and the low number of Linear Accelerators available in our Department, schedules similar to the above-proposed radiotherapy regimen have been tested to treat LA-HNC. Here, we report our favorable experience with HypoAR for LA-HNC patients.
Patients and Methods
One-hundred twenty-four patients with LA-HNC treated prospectively with 3D-conformal or intensity modulated VMAT/IGRT HypoAR were analyzed. All patients gave written informed consent, and the study was approved by the local Ethics and Scientific Committee of (SD7/26-2-04 and SD36/34/28-9-06). Patient and disease characteristics are listed in Table I. Table II summarizes the treatment characteristics. The median follow-up of patients alive at the time of last follow-up was 24 months (range=6-106 months).
Patient and disease characteristics.
Treatment characteristics.
Radiotherapy details. For patients treated with 3D-conformal radiotherapy, irradiation was performed using a 6/18MV linear accelerator (ELEKTA) endowed with a multi-leaf collimator, after CT-simulation and conformal radiotherapy planning (Plato, Nucletron, Stockholm, Sweden). We used two different fractionation schemes: i. 3.5 Gy for a total of 14-15 fractions to deliver the whole planned dose within 26 days (insertion of a split of 1 week after the first two weeks of therapy) and, ii. 2.7 Gy × 21-22 fractions in 30 days. A new CT-simulation and treatment planning was performed to shield the spinal cord after eight fractions of 3.5 Gy or 14 fractions of 2.7 Gy. Supraclavicular/lower neck areas were irradiated through anterior/posterior fields, receiving 11 fractions of 3.5 Gy or 14-15 fractions of 2.7 Gy. Involved node areas received a higher dose (12-15 fractions of 3.5 Gy or 18-20 fractions of 2.7 Gy). The distribution of radiotherapy schedules according to primary tumor location is shown in Table II.
For intensity-modulated image-guided IGRT/VMAT radiotherapy, multiple targets receiving different fractionation were designed. The treatment plans were produced at Monaco TPS version 5.1 (Elekta, Stockholm, Sweden) and therapy. They were delivered by a 6MV ELEKTA Infinity™ Linear Accelerator (Elekta, Stockholm, Sweden) with an Agility™ head (Elekta, Stockholm, Sweden) and multileaf collimator (MLC) featuring 5mm leaves at the isocenter. The gross tumor received 20-22 fractions of 2.5-2.7 Gy. Involved nodal areas received 2.5 Gy x 20-22 fractions, while uninvolved node areas 2.1 Gy × 22 or 2.2 × 20 fractions. During therapy, patients were re-evaluated with a new simulation followed by re-planning, when clinical or IGRT-detected shrinkage of the tumor demanded planning adjustments. The distribution of radiotherapy schedules according to primary tumor location is shown in Table II.
The structures outlined included the gross tumor volumes (GTV), the clinical target volumes (CTV) and planning target volumes (PTV) of the regions of interest. Contouring of organs at risk (OAR: eyes, lenses of eyes, larynx, parotids, submandibular and spinal cord) was performed. A mean margin of 5 mm (0.2-10 mm) was applied to delineate the PTVs from CTVs. The cost functions that were used for PTVs were two target penalties and a quadratic overdose. The first target penalty was set to prescribe 95% of total dose to 98% of minimum volume in order to have sufficient coverage and the second one was set to prescribe 100% of total dose to 50% of minimum volume in order to control the mean dose of the target. Quadratic overdose cost function was used for controlling the maximum dose of PTVs and was set as 100% of the maximum dose a with root mean square (RMS) of 50 cGy. In terms of dosimetry, for dose constrains in OARs, we used the QUANTEC criteria adapted for head and neck treatment (11, 12). In order to assess the biological dose in critical organs according to QUANTEC, all relevant Dose Volume Histograms DVHs derived from the hypofractionated schedules representing OARs were transformed into equivalent histograms by using a Niemierko model as described in a previous publication (13).
Radiobiological analysis. The ‘biological equivalent normalized total dose’ (NTD) was calculated using the formula proposed by Maciejewski (14) as follows: NTD=D ((α/β + d)/(α/β + 2)), where ‘D’ is the total physical dose, ‘d’ the dose per fraction and α/β is the tissue specific α/β-ratio. The NTD corrected for overall treatment time was calculated using a previously proposed formula (15), NTD(T)= D ((α/β + d)/(a/b + 2)) + λ(Tc-To), where Tc is the number of days required for the delivery of the NTD using a conventionally fractionated scheme, To is the number of days required for the delivery of the current scheme, and ‘λ’ is the estimated daily radiation dose consumed to compensate for rapid tumor repopulation. For cancer tissues, an α/β-ratio ranging between 4-10 Gy was considered. We also assumed a median ‘λ’ value of 0.2 Gy/day for late responding normal tissues and 0.4-0.8 Gy/day for cancer cells (16). The radiobiological analysis of the schedules applied is shown in Table III.
Radiobiological analysis of the HypoAR schedules applied.
Concurrent chemotherapy. Induction chemotherapy with 2-3 bi-weekly cycles of cisplatin/5-fluorouracil, cisplatin/cetuximab, or docetaxel/cisplatin/5-fluorouracil was offered to 108 patients (Table III). Subsequently, patients received concurrent chemoradiation with cisplatin (35-40 mg/m2 per week) and/or cetuximab 250 mg/m2/week (17). In patients with poor performance status, chemotherapy was omitted. Amifostine was applied subcutaneously daily before each radiotherapy fraction, in 60/124 patients.
Patient support and treatment delays. Since, in our Institute, no gastric tubes are routinely applied for the nutrition of our HNC patients undergoing radiotherapy, the introduction of 1- or 2-week breaks is enforced when dysphagia grade 3 develops. Meticulous oral hygiene with tooth brushing and mouthwashes with chlorhexidine is recommended throughout the therapy. Supplemental nutrition with high protein/calorie drinks is also used. Development of oropharyngeal fungal infection is treated with posaconazole suspension, 200 mg × 4 per day, till the end of radiotherapy. Analgesics (paracetamol with codeine phosphate combination) are also used to alleviate symptoms. Consumption of 1L of chamomile tea (at room temperature) per day is also recommended to support patients’ hydration and swallowing function.
Pre-treatment and treatment evaluation. Baseline studies included physical examination, blood tests and a complete biochemical profile. These were repeated weekly during therapy. Computerized tomography (CT-scan) or PET-SCAN was performed before radiotherapy. Radiation toxicity was monitored daily during radiotherapy, weekly for one month following the end of radiotherapy, at 3-months and 6-monthly after that. The NCI (National Cancer Institute) Common Toxicity Criteria Version 4.0 scale was used to score acute radiation toxicity. The LENT-SOMA toxicity scale was used to score late radiation sequel.
Response to treatment of measurable lesions was assessed with CT-scan 2 and 4 months after treatment completion, and 6-monthly thereafter. CR was defined as a 95-100% reduction of measurable lesions. Any residual scar measuring less than 5% of the initial tumor volume that does not progress for at least four months following response documentation was considered a complete response. Similarly, partial and minimal response refers to 50-95% and 25-49% reduction of tumor dimensions, respectively. A small reduction of tumor dimensions between 0-24% that lasted at least two months after response documentation, was considered a stable disease. All other cases were considered progressive disease, regardless of the initial response.
Statistical analysis. Statistical analysis and graph presentation were performed using the GraphPad Prism 7.0 package. The chi-square and Fisher’s exact two-tailed tests were used for testing relationships between categorical tumor variables. Locoregional control (time to locoregional disease progression following tumor regression) curves were plotted using the method of Kaplan–Meier. p-Values <0.05 were considered statistically significant.
Results
Radiation-induced toxicities. A direct index of the severity of acute toxicities in the current study was the enforcement and duration of treatment delays. For laryngeal carcinomas, this ranged from 0-21 days (mean value 4.3 days). Oropharyngeal mucositis grade 3 complicated or not with fungal infection was the cause of delays in all patients. Protraction of the overall treatment time beyond one week was enforced in 18/57 cases. There was no case of fatal acute toxicity. Regarding late toxicities, these concerned laryngeal edema grade 3 noted in 5/57 cases, dysphagia grade 2 in 2/57, and tracheoesophageal fistula creation in 1/57 cases.
For the rest of tumor locations, the delays in treatment completion, related to acute toxicities, ranged from 0-30 days (mean 4.5 days). Again, oropharyngeal mucositis grade 3 caused treatment delays, while there was no grade 4 toxicity. Protraction of the overall treatment time beyond one week was enforced in 6/19 nasopharyngeal cancer patients and 15/48 in the rest of patients Regarding late radiation toxicities, pharyngeal fibrosis and dysphagia grade 2 and 3 were recorded in 2/67 patients. Fibrosis grade 2 at the neck area corresponding to pre-existing large lymph nodes, where high radiation dose was delivered, was a common finding, but no severe fibrosis or necrosis was noted.
Response rates. Table IV shows the response rates obtained, as assessed two months after the end of radiotherapy. For patients with laryngeal cancer, the CR-rate ranged from 69% to 81% according to the dose per fraction, but no significant difference between the three radiotherapy schedules was noted (p=0.49). Similarly, there was no difference in the group of patients with nasopharyngeal tumors (p=0.32). In the rest of the patients, the CR-rate was significantly better in patients treated with the 3.5 Gy fractionation (p=0.02).
Response rates after radiotherapy according to the dose per fraction and overall radiotherapy time delays.
Table IV provides an analysis of response rates according to radiotherapy delays (less than one week vs. more than one week). More than one week of delay for laryngeal cancer patients resulted in an 18% reduction of CR-rates, but the difference did not reach significance (p=0.11). A similar effect was noted for nasopharyngeal cancer patients (p=0.15). No significant difference in terms of CR-rates was noted in the rest of the patients (p=0.44).
Loco-regional control. The local/regional progression-free survival (LPFS) of patients was assessed using the Kaplan–Meier curves. Figure 1A shows the LPFS stratified for major tumor locations. Nasopharyngeal cancer patients showed a better LPFS, as expected, although the difference did not reach significance (p=0.11). Figure 1Β focuses on the role of dose per fraction in laryngeal cancer, the largest tumor group in the current study. The LPFS seemed to be worse for fractions of 3.5 compared to lower fractions (p=0.10), but the group of patients treated with the 3.5Gy fractionation was too small. According to the overall radiotherapy time delays (less vs. more than one week), the analysis showed a marginal, not statistically significant, loss of efficacy with time prolongation (p=0.37), Figure 1C. Analysis for other tumor locations (excluding laryngeal and nasopharyngeal cancer) according to the dose per fraction showed a marginal benefit from larger doses per fraction (p=0.06); Figure 1D.
Local progression-free survival, plotted using the Kaplan–Meier method, was stratified according to: (A) primary tumor location, (B) overall treatment time delays in laryngeal cancer patients, (C) dose per fraction in laryngeal cancer patients and, (D) dose per fraction in non-laryngeal/non-nasopharyngeal cancer cases.
Amifostine and time delays. In the laryngeal group of cancer patients, delays exceeding one week were noted in 3/21 patients receiving amifostine vs. 15/36 patients who did not (p=0.04). In the nasopharyngeal cancer group, delays were noted in 2/8 vs. 4/11 patients receiving and not-receiving amifostine, respectively (p=0.97). For the rest of patients, out of 31 amifostine-treated patients, eight experienced more than a 1-week delay vs. 7/17 who did not receive amifostine (p=0.33). Overall, amifostine significantly protected patients against prolonged time delays (p=0.03).
Discussion
The role of accelerated tumor repopulation during radiotherapy has been well established, and JF Fowler suggested that an overall treatment time of 4-6 weeks would improve the radiotherapy efficacy (18). Trott et al. suggested that between the 3rd and 7th week of conventionally fractionated radiotherapy 0.5-0.7 Gy (out of the 2 Gy fraction) are consumed to compensate for rapid repopulation (19). Based on a radiobiological analysis of a large set of clinical data, Shuryak et al. suggested that the last five fractions of a conventional RT scheme do not enhance disease control. These simply compensate for increase accelerated cancer cell growth (20).
Hyperfractionated accelerated radiotherapy (twice or thrice-a-day) or patient irradiation during weekends have shown, indeed, better outcomes (21, 22). Irradiating patients two to three times a day, or at weekends, is certainly a cumbersome task that renders such schemes less appealing to radiotherapy departments. Standard fractionation combined with cisplatin (or cetuximab) remains the worldwide accepted treatment policy. A cumulative dose of 200 mg/m2 of cisplatin during radiotherapy is considered adequate, whether given as weekly or an every-three-week scheme (23). Of interest, in this later referenced analysis by Szturz et al., altered fractionation combined with high dose cisplatin seemed to offer improved survival.
Acceleration of radiotherapy could be easily achieved by using hypofractionation. Radiation oncologists, however, are reluctant to use such schemes, as the anticipated increase of late radiotherapy toxicities demands reduction of the total physical dose. Nevertheless, the biological dose can be accurately calculated by applying the linear-quadratic model for a 4 Gy α/β-ratio characterizing normal tissues (2 Gy for the spinal cord). By doing so and considering a median α/β-ratio of 10 Gy for cancer tissues, it is believed that the biologically active dose to the tumor diminishes. This, however, is a disputable concept for two main reasons. First, the individual tumor α/β-ratio is unknown. Highly hypoxic, highly senescent, or intrinsically radio-resistant cancer cells with large dose-response curve shoulders, thriving in large tumors, may have a far lower α/β value and increased resistance to low doses per fraction. Second, highly proliferating tumors or tumors able to undergo rapid tumor repopulation during radiotherapy would suffer radiation damage mainly dependent on radiotherapy’s time-density. The above, heretical for many colleagues, hypothesis is strongly supported by Shuryak, Hall and Brenner’s recent analysis suggesting that HypoAR applying around 3Gy per fraction in 4 weeks would increase the local control rates from 35% to 52.7% compared to conventional radiotherapy (10).
In the current study, we report results of a cohort of 124 patients with LA-HNC treated with HypoAR schedules, using 2.5-3.5 Gy per fraction, planned to deliver the total radiotherapy dose within 28-30 days (4-4.5 weeks). Cisplatin and/or cetuximab chemotherapy was concurrently applied. This schedule matches the one suggested by Shuryak et al. Radiobiological analysis, including time-correction, shows that these schedules deliver a biological dose between 58-66 Gy to early responding normal tissues (α/β=10 Gy), which is lower than the one provided by conventionally fractionated schemes (66-70 Gy). For late responding tissues included with the PTV (α/β=4 Gy) the biological radiation dose was between 62-69 Gy. This dose is within the range of the one delivered with standard fractionation. The minimum biological dose calculated for tumors (α/β=10 Gy) is 62 Gy, and the maximum (calculated for α/β=4 Gy) was 80Gy (depending upon the λ-factor considered). Thus, HypoAR is expected to be more or less effective depending upon the individual tumor α/β-value and the λ-value, which, alas, is impossible to predict, as yet.
Our study analyzed early toxicities showing patterns similar to those expected by standard radiotherapy. The rate of the severe late toxicities was well below 5%. These clinical results are along with the predicted toxicities from the radiobiological analysis performed herein. The complete response rates obtained were 73%, 84%, and 67% in patients with laryngeal, nasopharyngeal or other tumors, respectively. The 3-year loco-regional progression-free survival was 58%, 73%, and 55%, respectively. Such figures are at least similar to the ones expected by non-hypoAR regimens. Further analysis, according to the dose per fraction, showed that the 3.5 Gy/day schedule was slightly better, and this reached significance in non-laryngeal, non-nasopharyngeal tumors.
As gastric tubes for patient feeding during radiotherapy for head-neck patients is not the standard approach in Greece, we had to deal with inevitable treatment interruptions. Delays of more than one week were enforced in 31% of patients. Loss of any benefit from acceleration, due to a 3-week delay, is expected to have occurred in 5.6% of patients. Administration of amifostine significantly protected against prolonged delays. Analysis of the response rate and survival showed a reduction in radiotherapy efficacy for delays beyond one week, although the difference did not reach statistical significance. This shows that the acceleration of therapy is, indeed, an essential factor in HypoAR. However, it may be that concurrent chemotherapy may reduce the adverse impact of time factors, either by targeting more effectively highly proliferating cancer cells during the repopulation phase or by better sensitizing cancer cells to larger than conventional radiotherapy fractions. This latter hypothesis is supported by the recorded slightly higher efficacy of larger (3.5 Gy) fractions. A recent meta-analysis shows that concurrent conventional chemo-radiotherapy was superior to hyper-fractionated radiotherapy (without chemotherapy), which may also support chemotherapy’s role in reducing the impact of rapid tumor repopulation (24).
HypoAR is used worldwide as a palliative radiotherapy regimen for LA-HNC patients with poor performance status (25). The clinical data available on the usage of HypoAR as a radical radiotherapy scheme are limited. A feasibility study by Jacinto et al. on twenty patients with LA-HNC treated with cisplatin-supported HypoAR (2.75 Gy per fraction) showed good tolerance and a feasible median overall treatment time of 29 days (26). A hypofractionated non-accelerated regimen applying 3Gy per fraction and chemotherapy exhibited acceptable toxicity and 51% 1-year progression-free survival in patients with LA-HNC (27). In the current COVID-19 pandemic era, Huang et al. reported a trial of definitive radiotherapy, without chemotherapy, delivering 25 fractions of 2.4 Gy, suggesting acceptable tolerance and results similar to conventional radiotherapy (28).
Our study provides evidence that hypoAR chemoradiotherapy is feasible, with acceptable early and late radiotherapy sequels and high complete response rates. A larger than 2Gy fraction to the tumor area can be easily given daily with concomitant boost techniques, in the current era of image-guided and intensity-modulated radiotherapy, reducing the overall treatment time down to 4-5 weeks. Radiobiological analysis supports that the expected toxicity of HypoAR should be low, and that a benefit, in terms of anti-tumor radiotherapy efficacy, should be expected. As the benefit from HypoAR depends on the α/β-value of each tumor, any superiority in terms of overall efficacy should depend on the median value of α/βs characterizing LA-HNCs. Unlike prostate and breast cancer, this value is unknown for LA-HNC. For early laryngeal cancer, HypoAR is considered the standard therapy, and clinical data suggest a higher efficacy compared to conventional fractionation (9), which favors the assumption that the median α/β in head-neck cancer is lower than believed. Large randomized trials are needed to investigate the HypoAR hypothesis for LA-HNC.
Our clinical experience with hypoAR regimens confirms feasibility, good efficacy, and tolerance in head-neck malignancies. HypoAR is also a better than the ConvRT model to test the cytoprotective effectiveness of amifostine, as prolonged administration of the agent is avoided, and the dose of amifostine is concentrated to support far fewer fractions of RT. Accelerated hypofractionation, reducing the days of radiotherapy by 30%, is a convenient method for both patients and overloaded departments, minimizing the cost of therapy. Following the publication by Shuryak et al., sound biological rational supports the conduct of randomized clinical trials, anticipating the establishment of HypoAR as a safe, effective and convenient regimen. Our clinical experience from a single arm prospective study supports this proposal.
Footnotes
Authors’ Contributions
Ioannis M. Koukourakis: Data collection, analysis, writing of the paper; Anna Zygogianni: Data analysis, writing of the paper; Vassilios Kouloulias: Data analysis, writing of the paper; George Kyrgias: Data analysis, writing of the paper; Marianthi Panteliadou: Radiotherapy planning, treatment of patients, data collection, writing of the paper; Christos Nanos: Radiotherapy planning, writing of the paper; Ioannis Abatzoglou: Radiotherapy planning, writing of the paper; Michael I. Koukourakis: Conception, design, analysis, treatment of patients, writing of the paper.
Conflicts of Interest
There are no conflicts of interest to report regarding this study.
- Received November 21, 2020.
- Revision received November 30, 2020.
- Accepted December 2, 2020.
- Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.