Carcinoma of the Esophagus and Gastroesophageal Junction – Justification of Indicating Proton Therapy

Radiation Therapy Strategy

Determining a target volume during irradiation of the esophagus is based on several specifics:

• Primary tumor (squamous-cell cancer and adenocarcinoma) is predominantly spread via the lymphatic route. Dissemination “per continuitatem” is both longitudinal and radial.
• In esophageal tumors invading the submucosa, i.e. from stage Ib tumors, the risk of involvement of regional lymph nodes at the time of diagnosis sharply increases to 47% and more.
• Specific anatomy of lymphatic drainage in the esophageal submucosa, which is not segmental, allows longitudinal spreading over larger distances until tumor cells reach the sentinel lymph node. Tributary areas are large and difficult to define.
• Some lymphatic vessels drain directly into the thoracic duct without being filtered through a lymph node.
• Residual involvement of lymph nodes in the resected specimen after neoadjuvant radiotherapy is a predictor of relapse and survival. Therefore, the correct inclusion of high-risk nodal regions in the irradiated volume is important for preoperative radiotherapy and independent irradiation of the esophagus.

For these reasons, the target volume in radical radiotherapy should include:

• the primary tumor area (or anastomoses during postoperative irradiation) with areas of potential radial and longitudinal invasion;
• areas of demonstrably affected lymph nodes;
• large lymphatic areas at risk of involvement – “elective irradiation of lymphatics”.

Elective irradiation of lymphatics is a circumstance at the center of attention when irradiating esophageal tumors. In clinical studies, which demonstrated the efficacy of radiochemotherapy, various areas were included in the elective irradiation of lymphatics. According to the current consensus, it is beneficial to include in the target volume all the areas with a risk higher than 15-20%. The risks of lymph node involvement, depending on the site of the primary tumor in the esophagus, has been described in several studies based on lymphadenectomy findings. Marked differences are seen in the quantification of risks. The reported differences suggest some uncertainty in risk classification and the non-homogeneity of clinical trials with respect to study groups, which included mostly squamous-cell carcinoma. In contrast, no clear differences have been demonstrated between adenocarcinoma and squamous-cell carcinoma in the risk of lymphatic area involvement.

The distribution of risks, according to the sections of esophageal involvement in the largest referenced group, is schematically shown in Figure 1. The distribution of risks shows how large the volume of elective irradiation of lymphatics requires at risk above 15%. In general, the rule of including two adjacent floors in the irradiated volume can also be applied. For example, for tumors of the middle thoracic region, a large nodal area from the cervical to the upper abdominal nodes will be included in the volume.

Figure 1: Risk of involvement of nodal areas depending on the primary location of the tumor.

Advantages and Results of Proton Therapy

Application of proton irradiation in consensual protocol therapy of tumors of the esophagus has been tested at several sites in the world, especially in Japan and USA. Published data include dozens of treated patients. Ie. publications are phase II trials, rarely at the level of phase III studies.
You can derive some conclusions:

• Proton therapy allows a standard dose of 70 Gy, probably even higher. (They are referenced as the maximum dose of 98 Gy, median dose 79 Gy in the study).
• Proton therapy can be safely applied with standard concomitant chemotherapy. (Safety of therapy is documented in a recent, comprehensive study of 62 patients).
• The outcome of irradiation as compared with photon therapy is similar, but not inferior. Probably is even higher (e.g. 89% achieving a complete regression, 5-year survival over 20% -30%) superiority. Naturally, comparison of a randomized study is not available (probably from an ethical point of view will never be).
• Toxicity of proton radiation is lower. Higher levels of chronic toxicity are only about 10%. Comparative studies of realized irradiation plans are demonstrating at risk organs very significant differences in integral doses.
• Proton therapy allows safe elective irradiation of lymphatics at risk even with higher dosages.
• The favorable proton irradiation parameters make it possible to change standard fractionation regimens (hypofractionation, concomitant boost (9), etc.) and safely reduces the total time of irradiation. Secure hyperfractional mode with doses up to 3.6 Gy/fraction has been demonstrated.

Figure 2: Example of an irradiation plan and dose distribution to individual organs. It is clear that a significantly lower or zero dose is applied to healthy tissues during proton radiotherapy.

Photon Plan

Proton Plan

The proximity of radiosensitive organs such as lungs, heart, spinal cord, liver, kidneys and potentially thyroid gland and a complex geometric shape of the irradiated volume, markedly complicate the achievement of an effective therapeutic range. The risks of late adverse effects that may result in failure of the respective organs are of vital importance. Limited integral dose or maximum dose to the respective organs (“dose constraints”) are listed in the following table:

Table 1: Obligatory “dose constraints” for irradiation of esophageal tumors.

Limitations of Current Radiation Therapy – Technical and Biological Aspects

Standard preoperative irradiation of a localized esophageal cancer up to a total dose of 50 Gy in 25 fractions, including elective irradiation of lymphatics at 15% risk by photon therapy is difficult and requires the IMRT technique. The geometric shape of the irradiated volume is complex and includes multiple concavities. Even with the use of IMRT, it is difficult to adhere to the dose constraints specified in the above table. When increasing the dose up to a total of 70 Gy to the area of confirmed involvement (outside the volumes of elective irradiation), the difficulty is much higher even when using the IMRT technique.

Radiochemotherapy of esophageal cancer usually has acute and late side effects. The severity of both increases depending on the preoperative approach. The timing of surgery 4 to 6 weeks after the end of radiochemotherapy provides a short time window for the resolution of acute side effects. The risk is a delay of the procedure or permanent inability to undergo the resection procedure. Certain procedures, including thoracotomy and mediastinal lymphadenectomy, are associated with postoperative requirements as to the cardiorespiratory capacity, which may be impaired by the development of chronic toxic effects, with maximum impairment in the postoperative period. When using standard techniques of photon radiotherapy (IMRT, 3DCRT), the risk of any complications is up to 75%.

Toxicity of Radiotherapy

The risk of chronic adverse reactions in particular is clearly related to the adherence to the aforementioned “dose constraints”. Considering the increasing risks, various limiting integral doses can be defined for the respective organs.

• Acute side effects include in particular transient esophagitis with dysphagia and subsequent impaired nutrition, which may potentially result in refractory cachexia.
• Other common side effects are acute dysphagia of varying degrees, mucosal bleeding, leukopenia and thrombocytopenia. In major studies, any acute toxicity of grade 3-4 was recorded in 50-66% of patients.
• The main complication that clearly rules out any further surgical procedure is perforation of the esophagus.
• Chronic side effects most commonly include esophageal stenosis with a risk of up to 60%. Dilation or stent implantation (i.e. after independent radiochemotherapy) is necessary in 15-20% of patients.
• Chronic pulmonary side effects have been reported with a risk of about 18% and appear as post-radiation pneumonitis with subsequent development of pulmonary fibrosis and functional limitations. Development of pneumonitis is a serious complication in the postoperative period (after thoracotomy) with potentially fatal consequences.

Table 2: Structure for individual dose/organs.