Skip to main content
Download PDF

Dosimetric rationale and preliminary experience in proton plus carbon-ion radiotherapy for esophageal carcinoma: a retrospective analysis

Radiation Oncology volume 18, Article number: 195 (2023) Cite this article

Abstract

Background

Concurrent chemoradiotherapy has been standard of care for unresectable esophageal carcinoma. There were no reports on proton radiotherapy (PRT) plus carbon-ion radiotherapy (CIRT) with pencil beam scanning (PBS) for esophageal carcinoma. This study evaluated the tolerability and efficiency of proton and sequential carbon-ion boost radiotherapy for esophageal carcinoma.

Methods

From April 2017 to July 2020, 20 patients with primary esophageal carcinoma at stages II–IV were treated with PRT plus sequential CIRT with PBS. A median relative biological effectiveness-weighted PRT dose of 50 Gy in 25 fractions, and a sequential CIRT dose of 21 Gy in 7 fractions were delivered. Respiratory motion management was used if the tumor moved > 5 mm during the breathing cycle. A dosimetric comparison of photon intensity-modulated radiotherapy (IMRT), PRT, and CIRT was performed. The median times and rates of survivals were estimated using the Kaplan–Meier method. Comparison of the dose-volume parameters of the organs at risk employed the Wilcoxon matched-pairs test.

Results

Twenty patients (15 men and 5 women, median age 70 years) were included in the analysis. With a median follow-up period of 25.0 months, the 2-year overall survival and progression-free survival rates were 69.2% and 57.4%, respectively. The patients tolerated radiotherapy and chemotherapy well. Grades 1, 2, 3, and 4 acute hematological toxicities were detected in 25%, 30%, 10%, and 30% of patients, respectively. Grades 3–5 acute non-hematological toxicities were not observed. Late toxicity events included grades 1, 2, and 3 in 50%, 20%, and 10% (pulmonary and esophageal toxicity in each) of patients. Grades 4–5 late toxicities were not noted. PRT or CIRT produced lower doses to organs at risk than did photon IMRT, especially the maximum dose delivered to the spinal cord and the mean doses delivered to the lungs and heart.

Conclusions

PRT plus CIRT with PBS appears to be a safe and effective treatment for esophageal carcinoma. PRT and CIRT delivered lower doses to organs at risk than did photon IMRT. Further investigation is warranted.

Background

Esophageal carcinoma is the seventh most common malignancy and the sixth leading cause of cancer-related deaths worldwide [1]. In China, it ranks the sixth and fourth, respectively [2]. In contrast to adenocarcinoma, which is prevalent in European and American developed countries, squamous-cell carcinoma (SCC) is the leading (> 90%) type of malignant esophageal tumor in China. Compared to adenocarcinoma, SCC is more aggressive and exhibits more extensive lymph node metastasis and local infiltration and a worse prognosis [3, 4].

Recently, definitive concurrent chemoradiotherapy with a radiotherapy dose of 50–50.4 Gy has been considered the standard treatment for locally advanced esophageal carcinoma that is unresectable due to tumor position or invasion of surrounding tissues/organs and for those who cannot tolerate or refuse surgery [5]. An increased dose (e.g., more than 60 Gy) did not confer superior survival in esophageal carcinoma in clinical studies, [6] and toxicities induced by treatment might be a partial explanation. Technical improvements in highly conformal therapy translate into an increased radiation dose without increased treatment-related toxicities, which was expected to improve clinical outcomes in these patients.

A new type of treatment, particle (proton and carbon ion) radiotherapy (RT), presents advantages in physics over photon therapies. Multiple studies comparing dosimetric distributions have demonstrated that in esophageal carcinoma, particle beams can deliver a higher dose to the tumor while sparing the healthy organs at risk (OARs) such as the heart and lungs, thereby reducing treatment-related cardiopulmonary toxicity [7,8,9]. A retrospective study of proton radiotherapy (PRT) found improved clinical survival compared to photon RT and similar treatment-related toxicities in locally advanced esophageal carcinoma [10]. Moreover, a prospective trial showed that PRT and photon RT produced similar clinical survival; however, a reduced risk and severity of adverse effects were observed in the former [11].

Additionally, carbon ions produce more severe biological damage than do protons or photons owing to their higher linear energy transfer (LET) and could theoretically be more effective for radio-resistant tumors [12]. In the last 30 years, carbon-ion radiotherapy (CIRT) has produced significant clinical results in bone and soft-tissue sarcomas, head and neck cancers, hepatocellular carcinoma, prostate cancer, locally advanced cervical squamous-cell carcinoma, recurrent rectal cancer, and lung cancer [13,14,15,16,17,18,19,20,21,22]. Although no reports of definitive CIRT in locally advanced esophageal carcinoma have appeared, this treatment has been recommended for neoadjuvant radiotherapy in Japan [23]. Concerns of irreversible damage to the esophagus from neutron radiotherapy with high linear energy transfer in definitive radiotherapy or from CIRT alone should be considered cautiously [24]. Clinical practice using PRT combined with sequential CIRT for esophageal carcinoma was available at our center. Theoretically, PRT can eliminate radiosensitive tumor cells and mostly spare the OARs, and a sequential CIRT boost can effectively eliminate the remaining radio-resistant cells, which might provide satisfactory outcomes. We find no reports of PRT plus CIRT using pencil beam scanning (PBS) technology for esophageal carcinoma.

Therefore, this retrospective study aimed to investigate the safety and efficiency of PRT plus sequential CIRT boost in esophageal carcinoma and to perform a dosimetric comparison with photon intensity-modulated radiotherapy (IMRT).

Methods

Patient inclusion criteria

Patients who met the following criteria were included in this retrospective study: (1) pathological diagnosis of SCC, adenocarcinoma, or adenosquamous carcinoma; (2) stages I-III and IV (limited to patients with metastasis only to paraesophageal supraclavicular and cervical non-regional lymph node); (3) no esophageal surgery or thoracic irradiation prior to particle radiotherapy; and (4) received PRT combined with sequential CIRT boost therapy. The patients who received photon plus particle RT or a diagnosis of failure after surgery or RT were excluded from the study.

Treatment regimen

A total of four to six cycles of chemotherapy with fluorouracil- or platinum-based regimens were recommended during the whole treatment schedule. Highly recommended were thoracic PRT and sequential CIRT boost therapy with concurrent chemotherapy consisting of 5-fluorouracil (5-Fu) at 1800 mg/m2 continuous intravenous 72 hours on day 1; plus cisplatin (DDP) at 25 mg/m2, days 1–3; every 4 weeks; or paclitaxel at 135 mg/m2 or docetaxel at 75 mg/m2, day 1; plus cisplatin at 25 mg/m2, days 1–3; every 4 weeks.

Clinical practice of particle radiotherapy

Patients were set up routinely with a head-neck-shoulder or a trunk immobilization system according to the location of the esophageal carcinoma. The movement of tumor lesions and surrounding organs under free breathing was evaluated by fluoroscopy prior to simulation computed tomography (CT) scanning. If the motion of the tumor and/or surrounding OARs within the range of the particle trajectories was > 5 mm, respiratory gating or active breathing control was applied; otherwise, free breathing was used for simulation and particle delivery.

Gross tumor volume (GTV) was confirmed by CT, X-ray barium-meal imaging, positron emission tomography/CT (PET/CT), and gastroscopy. iGTV (internal gross tumor volume) was formed by combining GTVs across all 10 phases of respiratory gating. The high- or low-risk clinical target volume (CTV_highrisk or CTV_lowrisk) typically included 1 or 3 cm of the esophagus craniocaudally adjacent to the GTV/iGTV and a uniform 0.5–0.6 cm margin in all directions. The involved lymph nodes with a uniform expansion of 0.5-0.6cm was defined as CTV_highrisk. Prophylactic lymph nodal irradiation was not applied except that supraclavicular and superior mediastinal lymph node regions were irradiated as CTV_lowrisk for cervical esophageal carcinoma. The planning target volume (PTV) was generated by considering the range uncertainties and set-up errors. On average, the CTV was expanded 6 mm laterally, 6-8 mm at the entrance, and 8–12 mm in the distal direction of the beam view to form the PTV.

Radiation doses were prescribed as relative biological effectiveness (RBE)-weighted dose (DRBE) expressed in units of Gray (Gy) for both proton and carbon ions. The prescribed dose of PRT was delivered to CTV_lowrisk and CTV_highrisk, then the CIRT boost was delivered to CTV_highrisk only. The requirement for dose coverage was as follows: at least 99% of GTV/iGTV was covered by 95% of the prescription dose, 99% of the CTV was covered by 95% of the prescription dose to the CTV, and 90% of the PTV was covered by 90% of the prescription dose unless this would have exceeded the dose constraints.

The dose constraints for the OARs stipulated that the maximum dose (Dmax) of the esophagus and trachea should be less than 107% of the prescription doses. The Dmax to the spinal cord was also required to be < 45 Gy. The mean doses to both lungs were required to be < 14 Gy. If the doses to OARs could not meet these requirements, the dose coverage to the radiation targets was acceptably compromised.

The particle (carbon ion or proton) RT plans were designed using a commercial treatment planning system, Syngo PT Planning (Siemens Healthcare Systems, Erlangen, Germany), and intensity modulated PRT or CIRT (IMPT or IMCT) was realized with single beam or multiple-beam optimization strategy using pencil-beam techniques. The local effective model (LEM) was utilized to calculate the biological dose for carbon ion and 1.1 was set as the relative biological effectiveness for proton [25]. A fixed oblique gantry (45°) was applied for multiple-field irradiation, and usually two to three beams were applied via couch rotation. The full width at half maximum (FWHM) of 10.0 mm and the grid size of 2.0 mm were applied in the lateral beam spot density in both proton and carbon-ion plans. A range shifter, with 2 cm of thickness, was used for the shallow target in both proton and carbon-ion plans. Ripple filter of 3 mm-thickness that broadens the Bragg peak served as the energy modulator in the carbon-ion plans. Both proton and carbon-ion plans were calculated with 3 mm in grid. During particle therapy, CT review and dose distribution recalculation were performed weekly. If poor dose coverage or overdoses to OARs were evident, treatment replanning was required.

Dosimetric comparisons among IMRT, IMPT, and IMCT

Comparisons among plans were conducted for all enrolled patients. The same CTV_lowrisk and GTV/iGTV were used for the IMRT, IMPT, and IMCT plans, while the PTVs for IMRT were generated by adding a uniform margin of 6 mm to the CTV. A simulated IMRT plan was generated for comparison of dosimetric parameters, which was designed using Eclipse (Varian, Palo Alto, California, USA). Five to seven beams were occupied in the photon plans with a calculation grid size of 2.5 mm. For dosimetric comparison, the prescription DRBE of 69.3 Gy in 21 fractions was used for IMCT and IMPT plans. The same fractionation using absorbed dose was prescribed in IMRT plans and a similar target dose coverage was pursued. The OAR dose constraints used in the dosimetric study were the same for IMRT, IMPT, and IMCT as in clinical practice, which was described above for particle RT, except that the Dmax to the spinal cord was required to be < 50 Gy in IMRT plans.

The following parameters were extracted from the dose-volume histograms (DVHs): Dmax to the main bronchial tree (MBT, including the trachea, the carina, and the right and left main bronchi as far as the openings of the segmental bronchi) and spinal cord; the dose that 1% of the volume received (D1%) of the MBT and spinal cord; the percentage volume of the lungs and heart that received 5–60 Gy [V5–V60]; and the mean doses (Dmean) to each.

Follow-up and statistical analyses

Follow-up was conducted weekly during radiotherapy, every 3–4 months in the first and second year after radiotherapy, every 6 months in the third and fourth year, and every year thereafter. During radiotherapy, a physical examination and a complete blood count were conducted once a week (twice a week if concurrent chemotherapy was administered), X-ray barium-meal imaging was performed every 2 weeks, and hepatic/renal function was tested prior to concurrent chemotherapy. Physical examination, complete blood count, hepatic/renal function, X-ray barium-meal imaging, and CT were performed every post-RT medical visit. Gastrointestinal endoscopy was performed if clinical failure or any severe gastrointestinal side effect was suspected detected by physical examination, X-ray barium-meal imaging, CT, etc.

The following data were collected: (1) treatment toxicities quantified by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE); (2) treatment response as measured by CT scanning and X-ray barium-meal imaging, and any further PET/CT scanning and/or endoscopic or aspiration biopsy if needed; and (3) the rates and median times of overall survival (OS), progression-free survival (PFS), locoregional progression-free survival (LRPFS), and distant metastasis-free survival (DMFS). Observation of all events started from the initiation of radiotherapy until an event occurred or until the last follow-up, whichever came first.

The rates and median times of OS, PFS, LRPFS, and DMFS were estimated by the Kaplan–Meier method. The treatment planning DVH parameters were compared by the Wilcoxon matched-pairs test. The STATA statistical software package was used for statistical analyses (version 11.0; StataCorp LP, Texas, USA). A p-value < 0.05 was considered statistically significant.

Results

Patient characteristics

From April 2017 to July 2020, 21 consecutive patients who met the inclusion criteria received particle radiotherapy at our institution. One patient was lost to follow-up. Finally, 20 patients were included in this study. The characteristics of the study sample are summarized in Table 1.

Table 1 Characteristics and treatment details of patients with esophageal carcinoma included in this study (N = 20)
Full size table

All patients were pathologically confirmed as having SCC. All but three patients (85%) received chemotherapy. Among them, 14 (70%) patients received pre-RT chemotherapy, and 12 (60%) received post-RT chemotherapy with fluorinated pyrimidines (5-fluorouracil, capecitabine, S-1) or taxanes plus platinum. Nine (45%) received concurrent chemotherapy with taxanes plus platinum, except for one who received carboplatin monotherapy because of abnormal renal function. All patients received PRT plus sequential CIRT with a total DRBE of 71 Gy (range, 65–73.1) in 32 fractions (29–33). PRT was delivered at 50 Gy (range, 44–56) in 25 fractions (22–28). CIRT was administered at 21 Gy (range, 15–23.1) in 7 fractions (5–7), 3 Gy/fraction in 7 (5–7) fractions in 13 patients and 3.3 Gy/fraction in 7 fractions in seven patients, respectively.

Dosimetric comparison

The dosimetric parameters of the OARs in IMRT, IMPT, and IMCT for all patients are listed in Table 2 and illustrated in Fig. 1.

Table 2 Dosimetric parameters of the organs at risk in the three radiotherapy techniques studied
Full size table
Fig. 1
figure 1

The simulated dose distribution of three radiation techniques for esophageal carcinoma. (A) Intensity modulated carbon-ion radiotherapy, IMCT, (B) Intensity modulated proton radiotherapy, IMPT, and (C) Photon intensity-modulated radiotherapy, IMRT. The isodose of 65.84 Gy was 95% of the prescription dose, and is presented together with levels 60, 50, 40, and 30 Gy. Doses are presented as the RBE (relative biological effectiveness)-weighted dose

Full size image

An adequate coverage of the tumor target was achieved in all three plans. In addition, the dose distributions to the OARs were evidently lower in the IMPT and IMCT plans than in IMRT. IMPT and IMCT showed an apparent improvement in the Dmax to spinal cord, and in the Dmean to the heart and lungs compared to IMRT (p < 0.05). Of note, V5, V10, and V20 in the lungs and V5–V60 in the heart were significantly lower in IMPT and IMCT than in IMRT.

We observed a slightly higher Dmax to the MBT and a lower Dmax to the spinal cord in IMCT than in IMPT with statistical significance (p < 0.05). The Dmean and V30/V40 to the lungs and the Dmean and V5/V10/V30/V60 to the heart were slightly higher in IMCT than in IMPT (p < 0.05).

Treatment toxicity

All patients completed the full PRT and CIRT course. Except in instances of unplanned failure of the treatment system, RT was interrupted in six patients, comprising myelosuppression after chemoradiotherapy in four, bacterial pneumonia in one, and esophageal ulcer in one. The patients tolerated RT and chemotherapy well (Table 3).

Table 3 Treatment-related toxicities of proton and carbon-ion radiotherapy combined with chemotherapy
Full size table

Grades 3 and 4 acute hematological toxicities occurred in 10% and 30% of patients, respectively. No cases of grades 3–5 of acute non-hematological toxicity were observed. Severe late toxicities included one grade-3 pulmonary toxicity (tracheal stenosis) (5.0%) and one grade-3 esophageal toxicity (esophageal-pulmonary fistula).

Survival and failure patterns

With a median follow-up period of 25.0 months (7.5–56.4), the 1- and 2-year rates of OS, PFS, LRPFS, and DMFS were 80.0% (95% CI, 55.1–92.0%), 63.8% (38.6–80.8%), 72.4% (45.6–87.6%), 81.4% (52.3–93.7%); and 69.2% (43.8–84.9%), 57.4% (32.2–76.2%), 65.1% (37.6–82.9%), 81.4% (52.3–93.7%), respectively (Fig. 2). The median times of OS, LRPFS, and DMFS were not reached. The median PFS time was 28.2 months.

Fig. 2
figure 2

Survival probabilities of esophageal cancer patients after proton and carbon-ion radiotherapy. (Groups 1, 2, 3, and 4 delegate Overall survival, Progression free survival, Locoregional progression free survival, and Distant metastasis free survival.)

Full size image

At the last follow-up, 12 patients (60.0%) were alive, with a median follow-up period of 29.2 months (16.3–56.4). Among these patients, seven experienced recurrence, comprising four with locoregional failure, one with distant failure, and two with both locoregional and distant failure.

Discussion

In the current study, we delivered PRT plus CIRT with PBS to 20 patients with primary esophageal SCC. With a median follow-up period of 25.0 months, 2-year OS and PFS rates of 69.2% and 57.4%, respectively, were achieved with mild RT-related side effects in a cohort of patients with stage II–III and IV (limited to patients with metastasis only to paraesophageal supraclavicular and cervical non-regional lymph-node) and a median age of 70 years. PRT and CIRT produced lower doses to the OARs than did photon IMRT, notably as Dmax to the spinal cord and Dmean to the lungs and heart. Dosimetric comparison indicated a rationale for PRT and CIRT in esophageal carcinoma. PRT plus CIRT with PBS appears safe and effective for esophageal carcinoma in a short-term observation.

Concurrent chemoradiotherapy was recommended for patients with locally advanced esophageal carcinoma who were not candidates for resection or could not tolerate surgery, in keeping with its preferred status in such patients [26]. Photon radiotherapy concurrently with chemotherapy has shown efficiency and tolerability compared to photon radiotherapy alone against locally advanced esophageal carcinoma, with 2- and 3-year OS rates of 36% and 30% after combined chemoradiotherapy, compared to 10% and 0% in the radiotherapy-only group, respectively [27]. An RT dose of 50–50.4 Gy was demonstrated to be highly acceptable for patients with locally advanced esophageal carcinoma [5]. The 2-year OS rates were typically 36–55% in randomized studies and the highest, reported recently, was 67% [6, 27,28,29].

In trials of neoadjuvant chemoradiotherapy, [30,31,32] a complete response rate of 30–40% after 40–50 Gy was noted in esophageal carcinoma, indicating that an irradiation dose of 40–50 Gy is sufficient for one-third of esophageal carcinoma patients. However, for the remainder, a higher dose might be indicated if the attendant toxicity was tolerable. A population-based, propensity-score–matched analysis suggested that a higher irradiation dose (≥ 60 Gy vs. 50–50.4 Gy) might improve survival in patients with esophageal SCC [33]. However, a randomized study showed that a total dose of 64.8 Gy did not improve clinical outcomes compared with 50.4 Gy in locally advanced esophageal carcinoma and showed an extended treatment duration due to toxicity breaks and a decreased actual dose of fluorouracil [6]. Furthermore, a recent randomized study (ARTDECO) reported similar OS and LPFS rates between RT doses of 50.4 and 61.6 Gy [28]. Analysis of patients with esophageal carcinoma receiving PRT or IMRT showed that PRT and a Dmean of < 15 Gy to the heart are associated with a decreased incidence of severe (grade 3 or higher) cardiac events, and these events are associated with poorer OS (p < 0.05) [34]. These findings indicate that technical improvements in highly conformal therapy can be expected to improve clinical results in locally advanced esophageal carcinoma if they lead to an increased dose to targets without increased radiation exposure to the OARs (especially the heart).

Similar to our results, the literature also shows that protons and carbon ions can better protect normal tissues than can photons, specifically 3DCRT or IMRT, whether they are passive scattering protons or PBS beams. Compared to IMRT, PRT achieved a significant decrease with the passive scattering technique, especially a decline in the Dmax of the spinal cord, Dmean, V25, V30, V40, and V50 of the heart and Dmean, V5, V10, and V15 of the lungs (Table 4) [9]. CIRT with PBS (i.e. IMCT technique, similar to the technique used in our center) produced better dose homogeneity in the target volume and significantly lower doses to the heart, lungs, spinal cord, and skin in esophageal carcinoma than did photon 3DCRT or volumetric modulated arc therapy (VMAT, a variant of IMRT). Compared to VMAT, significant decreases were achieved with CIRT, especially in the Dmax to the spinal cord; Dmean, V10, V20, V30, and V40 to the heart; and Dmean, V5, V10, V20, V30, and V40 to the lungs [35].

Table 4 Dosimetric parameters of organs at risk in esophageal carcinoma treated with photon vs. particle radiotherapy
Full size table

To our knowledge, this is the first study to compare dosimetric parameters among IMPT, IMCT, and photon IMRT in esophageal carcinoma. Similar to Ling et al.’s study using the scattering technique, [9] in our study, PRT using the scanning technique produced a more apparent decline in V20 of the lungs than did IMRT. Compared with PRT using passive scattering, [10] the more advanced IMPT with PBS is associated with further dosimetric benefits in sparing the heart in radiotherapy for esophageal cancer and has also been reported as sparing the lungs and heart in radiotherapy for lung cancer [36]. CIRT using the scanning technique here produced results for esophageal cancer similar to those reported by Takakusagi et al., [35] which included a similar decline in the Dmax of the spinal cord, a decrease in the Dmean and V5–V60 of the heart, and a lesser decline in the Dmean and V5–V20 of the lungs. Those authors used the same PTV for photon and carbon-ion planning; in contrast, in this study, a larger PTV (beam-specific PTV) was applied as in routine clinical practice of particle therapy. Although a trend of better dose distribution to OARs was noted in PRT compared to CIRT planning, the differences were minor in this study.

By taking advantage of dose distribution, PRT led to either a lesser treatment-related toxicity burden than photon radiotherapy or an improvement in survivals for esophageal cancer [10, 11]. Xi et al. conducted a retrospective study of PRT and photon IMRT with a total dose of 50.4 Gy/28Fx concurrently with chemotherapy of fluorouracil and platinum/taxane in esophageal carcinoma [10]. PRT led to improved survival, with higher 5-year OS and PFS rates of 41.6% and 34.9% compared with photon radiotherapy rates of 31.6% and 20.4%, respectively. PRT also induced low severe toxicities compared with photon radiotherapy, with treatment-related severe toxicity of 39% vs. 47% (p > 0.05). Furthermore, a prospective phase-IIb randomized study of PRT mostly using a passive scattering technique vs. photon IMRT with a total dose of 50.4 Gy/28Fx concurrently with fluorouracil/taxane-based chemotherapy showed that PRT maintained similar OS and PFS rates (3-year OS, 51.2% vs. 50.8%; 3-year PFS, 44.5% vs. 44.5%). However, PRT was associated with a lower total toxicity burden [11]. Failure to improve clinical outcomes may be related to the passive scattering technique initially used and a lack of clinician experience with the new technology, similar to the lesson learnt with lung cancer. Compared to PRT, our study on IMPT followed by IMCT with a median total dose of 71 Gy (range: 65–73.1) in esophageal carcinoma produced a promising clinical outcome (2-year OS, 69.2% and 2-year PFS, 57.4%) with mild esophageal toxicities (5%). Severe esophageal and pulmonary toxicity rates of more than 20% were observed after photon RT and PRT with passive scattering in early patients, which included a severe late esophageal toxicity rate of 19–21% after photon RT and severe esophagitis and esophageal stricture rates of 11.4% and 9.8% after proton RT, respectively [6, 10, 27]. The clinical benefit of this treatment modality may be attributed to the dosimetric advantages of IMPT and IMCT when combined with PBS, which can further reduce the dose to normal tissue compared with passive scattering technique, thereby further reducing doses to the heart and thus the incidence of adverse events.

This study had some limitations. First, a definitive conclusion could not be drawn owing to the small sample size and the retrospective nature of the study. Second, our study delivered a wide range of dose prescriptions, attempting to balance toxicity and clinical efficacy. Finally, this study included patients with stage IV esophageal cancer (with metastasis only to paraesophageal non-regional lymph nodes, defined in AJCC, 8th edition), which hampered a definitive conclusion for locally advanced esophageal cancer. Currently, a large-scale prospective study to evaluate the efficacy and safety of PRT plus CIRT in locally advanced esophageal carcinoma is underway. We expect that the results will validate our findings.

Conclusions

This is the first study to investigate combined IMPT and IMCT for esophageal carcinoma. Our results demonstrated better sparing of OARs with mild toxicities compared to IMRT and showed promising OS and PFS rates. Further prospective studies with more patients are warranted.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available due to hospital policy but are available from the corresponding author on reasonable request.

Abbreviations

3DCRT:

3D conformal radiotherapy

CI:

Confidence interval

CIRT:

Carbon-ion radiotherapy

CT:

Computed tomography

CTCAE:

Common terminology criteria for adverse events

CTV:

Clinical target volume

D1% :

The dose that 1% of the volume received

Dmax :

Maximum dose

Dmean :

Mean dose

DMFS:

Distant metastasis-free survival

DRBE :

RBE-weighted dose

DVH:

Dose volume histogram

GTV:

Gross tumor volume

iGTV:

Internal gross tumor volume

IMCT:

Intensity modulated CIRT

IMPT:

Intensity modulated PRT

IMRT:

Intensity-modulated radiotherapy

LEM:

Local effective model

LET:

Linear energy transfer

LRPFS:

Locoregional progression-free survival

MBT:

Main bronchial tree

OAR:

Organ at risk

OS:

Overall survival

PBS:

Pencil beam scanning

PET:

Positron emission tomography

PFS:

Progression-free survival

PRT:

Proton radiotherapy

PTV:

Planned target volume

RBE:

Relative biological effectiveness

RT:

Radiotherapy

SCC:

Squamous-cell carcinoma

SUVmax :

Maximum standard uptake value

VMAT:

Volumetric modulated arc therapy

Vx:

Percentage volume of the lungs receiving ≥ x Gy of irradiation

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, 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. https://doi.org/10.3322/caac.21660.

    Article  PubMed  Google Scholar 

  2. Chen W, Sun K, Zheng R, Zeng H, Zhang S, Xia C, et al. Cancer incidence and mortality in China, 2014. Chin J Cancer Res. 2018;30:1–12. https://doi.org/10.21147/j.issn.1000-9604.2018.01.01.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Smyth EC, Lagergren J, Fitzgerald RC, Lordick F, Shah MA, Lagergren P, et al. Oesophageal cancer. Nat Rev Dis Primers. 2017;3:17048. https://doi.org/10.1038/nrdp.2017.48.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Siewert JR, Ott K. Are squamous and adenocarcinomas of the esophagus the same Disease? Semin Radiat Oncol. 2007;17:38–44. https://doi.org/10.1016/j.semradonc.2006.09.007.

    Article  PubMed  Google Scholar 

  5. Ajani JA, D’Amico TA, Bentrem DJ, Chao J, Corvera C, Das P, et al. Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice guidelines in Oncology. J Natl Compr Canc Netw. 2019;17:855–83. https://doi.org/10.6004/jnccn.2019.0033.

    Article  CAS  PubMed  Google Scholar 

  6. Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, et al. INT 0123 (Radiation Therapy Oncology Group 94 – 05) phase III trial of combined-modality therapy for Esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol. 2002;20:1167–74. https://doi.org/10.1200/JCO.2002.20.5.1167.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang X, Zhao KL, Guerrero TM, McGuire SE, Yaremko B, Komaki R, et al. Four-dimensional computed tomography-based treatment planning for intensity-modulated radiation therapy and proton therapy for distal Esophageal cancer. Int J Radiat Oncol Biol Phys. 2008;72:278–87. https://doi.org/10.1016/j.ijrobp.2008.05.014.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Welsh J, Gomez D, Palmer MB, Riley BA, Mayankkumar AV, Komaki R, et al. Intensity-modulated proton therapy further reduces normal tissue exposure during definitive therapy for locally advanced distal esophageal tumors: a dosimetric study. Int J Radiat Oncol Biol Phys. 2011;81:1336–42. https://doi.org/10.1016/j.ijrobp.2010.07.2001.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ling TC, Slater JM, Nookala P, Mifflin R, Grove R, Ly AM, et al. Analysis of Intensity-Modulated Radiation Therapy (IMRT), Proton and 3D conformal radiotherapy (3D-CRT) for reducing Perioperative Cardiopulmonary Complications in Esophageal Cancer patients. Cancers (Basel). 2014;6:2356–68. https://doi.org/10.3390/cancers6042356.

    Article  PubMed  Google Scholar 

  10. Xi M, Xu C, Liao Z, Chang JY, Gomez DR, Jeter M, et al. Comparative outcomes after definitive Chemoradiotherapy using Proton Beam Therapy Versus Intensity Modulated Radiation Therapy for Esophageal Cancer: a retrospective, single-institutional analysis. Int J Radiat Oncol Biol Phys. 2017;99:667–76. https://doi.org/10.1016/j.ijrobp.2017.06.2450.

    Article  PubMed  Google Scholar 

  11. Lin SH, Hobbs BP, Verma V, Tidwell RS, Smith GL, Lei X, et al. Randomized phase IIB Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for locally Advanced Esophageal Cancer. J Clin Oncol. 2020;38:1569–79. https://doi.org/10.1200/JCO.19.02503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schulz-Ertner D, Tsujii H. Particle radiation therapy using proton and heavier ion beams. J Clin Oncol. 2007;25:953–64. https://doi.org/10.1200/JCO.2006.09.7816.

    Article  PubMed  Google Scholar 

  13. Kamada T, Tsujii H, Blakely EA, Debus J, De Neve W, Durante M, et al. Carbon ion radiotherapy in Japan: an assessment of 20 years of clinical experience. Lancet Oncol. 2015;16:e93–e100. https://doi.org/10.1016/S1470-2045(14)70412-7.

    Article  PubMed  Google Scholar 

  14. Hu J, Huang Q, Gao J, Guan X, Hu W, Yang J, et al. Clinical outcomes of carbon-ion radiotherapy for patients with locoregionally recurrent nasopharyngeal carcinoma. Cancer. 2020;126:5173–83. https://doi.org/10.1002/cncr.33197.

    Article  PubMed  Google Scholar 

  15. Chen J, Lu JJ, Ma N, Zhao J, Chen C, Fan M, et al. Early stage non-small cell Lung cancer treated with pencil beam scanning particle therapy: retrospective analysis of early results on safety and efficacy. Radiat Oncol. 2019;14:16. https://doi.org/10.1186/s13014-019-1216-1.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Imai R, Kamada T, Tsuji H, Yanagi T, Baba M, Miyamoto T, et al. Carbon ion radiotherapy for unresectable sacral chordomas. Clin Cancer Res. 2004;10:5741–6. https://doi.org/10.1158/1078-0432.CCR-04-0301.

    Article  CAS  PubMed  Google Scholar 

  17. Matsumoto K, Imai R, Kamada T, Maruyama K, Tsuji H, Tsujii H, et al. Impact of carbon ion radiotherapy for primary spinal sarcoma. Cancer. 2013;119:3496–503. https://doi.org/10.1002/cncr.28177.

    Article  CAS  PubMed  Google Scholar 

  18. Combs SE, Nikoghosyan A, Jaekel O, Karger CP, Haberer T, Munter MW, et al. Carbon ion radiotherapy for pediatric patients and young adults treated for tumors of the skull base. Cancer. 2009;115:1348–55. https://doi.org/10.1002/cncr.24153.

    Article  PubMed  Google Scholar 

  19. Ishikawa H, Tsuji H, Kamada T, Akakura K, Suzuki H, Shimazaki J, Tsujii H, et al. Carbon-ion radiation therapy for Prostate cancer. Int J Urol. 2012;19:296–305. https://doi.org/10.1111/j.1442-2042.2012.02961.x.

    Article  PubMed  Google Scholar 

  20. Okonogi N, Wakatsuki M, Kato S, Shiba S, Kobayashi D, Kiyohara H, et al. Long-term outcomes of carbon-ion radiotherapy for locally advanced squamous cell carcinoma of the uterine cervix. Anticancer Res. 2018;38:457–63. https://doi.org/10.21873/anticanres.12244.

    Article  CAS  PubMed  Google Scholar 

  21. Shiba S, Okamoto M, Kiyohara H, Ohno T, Kaminuma T, Asao T, et al. Prospective observational study of high-dose carbon-ion radiotherapy for pelvic recurrence of rectal cancer. Front Oncol. 2019;9:702. https://doi.org/10.3389/fonc.2019.00702.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Takahashi W, Nakajima M, Yamamoto N, Yamashita H, Nakagawa K, Miyamoto T, et al. A prospective nonrandomized phase I/II study of carbon ion radiotherapy in a favorable subset of locally advanced non-small cell Lung cancer (NSCLC). Cancer. 2015;121:1321–7. https://doi.org/10.1002/cncr.29195.

    Article  CAS  PubMed  Google Scholar 

  23. Akutsu Y, Yasuda S, Nagata M, Izumi Y, Okazumi S, Shimada H, et al. A phase I/II clinical trial of preoperative short-course carbon-ion radiotherapy for patients with squamous cell carcinoma of the esophagus. J Surg Oncol. 2012;105:750–5. https://doi.org/10.1002/jso.22127.

    Article  PubMed  Google Scholar 

  24. Laramore GE, Davis RB, Olson MH, Cohen L, Raghaven V, Griffin TW, et al. RTOG Phase I study on fast neutron teletherapy for squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys. 1983;9:465–73. https://doi.org/10.1016/0360-3016(83)90062-7.

    Article  CAS  PubMed  Google Scholar 

  25. Krämer M, Scholz M. Treatment planning for heavy-ion radiotherapy: calculation and optimization of biologically effective dose. Phys Med Biol. 2000;45:3319–30.

    Article  PubMed  Google Scholar 

  26. Herskovic A, Martz K, al-Sarraf M, Leichman L, Brindle J, Vaitkevicius V, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med. 1992;326:1593–8. https://doi.org/10.1056/NEJM199206113262403.

    Article  CAS  PubMed  Google Scholar 

  27. Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA, Jr, Al-Sarraf M, et al. Chemoradiotherapy of locally advanced Esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85 – 01). Radiation Therapy Oncology Group JAMA. 1999;281:1623–7. https://doi.org/10.1001/jama.281.17.1623.

    Article  CAS  PubMed  Google Scholar 

  28. Hulshof M, Geijsen ED, Rozema T, Oppedijk V, Buijsen J, Neelis KJ, et al. Randomized study on dose escalation in definitive chemoradiation for patients with locally Advanced Esophageal Cancer (ARTDECO Study). J Clin Oncol. 2021;39:2816–24. https://doi.org/10.1200/JCO.20.03697.

    Article  CAS  PubMed  Google Scholar 

  29. Ai D, Ye J, Wei S, Li Y, Luo H, Cao J, et al. Comparison of 3 paclitaxel-based chemoradiotherapy regimens for patients with locally advanced esophageal squamous cell dancer: a randomized clinical trial. JAMA Netw Open. 2022;5:e220120. https://doi.org/10.1001/jamanetworkopen.2022.0120.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Yang H, Liu H, Chen Y, Zhu C, Fang W, Yu Z, et al. Neoadjuvant chemoradiotherapy followed by Surgery versus Surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phase III multicenter, randomized, open-label clinical trial. J Clin Oncol. 2018;36:2796–803. https://doi.org/10.1200/JCO.2018.79.1483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074–84. https://doi.org/10.1056/NEJMoa1112088.

    Article  PubMed  Google Scholar 

  32. Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE, Goldberg R, et al. Phase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and Surgery compared with Surgery alone for Esophageal cancer: CALGB 9781. J Clin Oncol. 2008;26:1086–92. https://doi.org/10.1200/JCO.2007.12.9593.

    Article  CAS  PubMed  Google Scholar 

  33. Chen CY, Li CC, Chien CR. Does higher radiation dose lead to better outcome for non-operated localized esophageal squamous cell carcinoma patients who received concurrent chemoradiotherapy? A population-based propensity-score matched analysis. Radiother Oncol. 2016;120:136–9. https://doi.org/10.1016/j.radonc.2016.04.042.

    Article  PubMed  Google Scholar 

  34. Wang X, Palaskas NL, Yusuf SW, Abe JI, Lopez-Mattei J, Banchs J, et al. Incidence and onset of severe cardiac events after radiotherapy for Esophageal cancer. J Thorac Oncol. 2020;15:1682–90. https://doi.org/10.1016/j.jtho.2020.06.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Takakusagi Y, Yoshida D, Kusano Y, Kano K, Anno W, Tsuchida K, et al. Dosimetric comparison between carbon-ion radiotherapy and photon radiotherapy for stage-I Esophageal cancer. In Vivo. 2021;35:447–52. https://doi.org/10.21873/invivo.12277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chang JY, Li H, Zhu XR, Liao Z, Zhao L, Liu A, et al. Clinical implementation of intensity modulated proton therapy for thoracic malignancies. Int J Radiat Oncol Biol Phys. 2014;90:809–18. https://doi.org/10.1016/j.ijrobp.2014.07.045.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This study was supported by the Shanghai Hospital Development Center Foundation (grant number SHDC12019X25); the Natural Science Foundation of Shanghai (grant number 20ZR1453300); the Shanghai Municipal Health Commission Funds (grant number 201940334, 202240052); and Shanghai Pudong New Area Health Committee (grant number PW2021A-35). The study sponsors had no involvement in the design of the study or in the collection, analysis, or writing of the manuscript.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai Key Laboratory of radiation oncology (20dz2261000), Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, 4365 Kang Xin Road, Shanghai, 201315, China

    Ningyi Ma, Jian Chen, Kai-Liang Wu, Jiade Lu, Guoliang Jiang & Jingfang Mao

  2. Department of Medical Physics, Shanghai Proton and Heavy Ion Center, Shanghai Key Laboratory of radiation oncology (20dz2261000), Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China

    Xue Ming

Authors
  1. Ningyi Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xue Ming
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jian Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kai-Liang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jiade Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Guoliang Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jingfang Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JM and KW designed the study. JM, NM, and JC collected, analyzed, and interpreted the patient data and drafted the manuscript. XM performed the dosimetric comparisons and statistical analysis and was a major contributor in writing the manuscript. JM, NM, KW, JL, and GJ edited the manuscript. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Jingfang Mao.

Ethics declarations

Ethics approval and consent to participate

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Shanghai Proton and Heavy Ion Center (approval number SPHIC-TR-THLC-2022-01 (RS)). Written informed consent was obtained from all patients for using their data.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, N., Ming, X., Chen, J. et al. Dosimetric rationale and preliminary experience in proton plus carbon-ion radiotherapy for esophageal carcinoma: a retrospective analysis. Radiat Oncol 18, 195 (2023). https://doi.org/10.1186/s13014-023-02371-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13014-023-02371-9

Keywords

Radiation Oncology

ISSN: 1748-717X

Contact us