Acute toxicity of definitive chemoradiation in patients with inoperable or irresectable esophageal carcinoma

Esophageal carcinoma is the eighth most common cancer worldwide [1]. The total incidence of esophageal cancer is rising, mainly as the result of a marked increase in the incidence of adenocarcinoma. It is often diagnosed in late stages, and approximately 50% of the patients have potentially curable disease.

In patients who are considered fit for surgery and have technically resectable disease the treatment of choice is surgical resection. Outcome of esophageal resection can be improved by multimodality treatment. A meta-analysis has shown significant benefit of chemoradiation followed by over surgery alone for both adenocarcinoma and squamous cell carcinoma. The hazard ratio for all-cause mortality with neoadjuvant chemoradiotherapy versus surgery alone was 0.81 (95% CI 0.70-0.93; p = 0.002), corresponding to a 13% absolute difference in survival at 2 years [2]. In the Netherlands the preferred radiochemotherapy regimen consists of carboplatin plus paclitaxel concurrent with 41.4 Gy of radiation, which is based on the results of the Dutch CROSS study which showed a median survival of 49.4 months in the chemoradiotherapy surgery arm versus 24 months in the surgery group. The chemoradiation regimen was well tolerated with 7% hematologic and 13% non hematologic grade 3/4 toxicities, mainly leukopenia and anorexia [3].

In contrast to patients with resectable disease, patients staged irresectable (T4N0-1 M0) by endoscopic ultrasonography (EUS) have a very poor prognosis [4, 5]. Primary surgery does not prolong survival and patients can be treated with chemotherapy, radiation therapy or best supportive care [6, 7].

Based on the results of the RTOG 8501 [8] chemoradiotherapy is superior compared to radiotherapy alone. In this prospective randomized clinical trial, patients with squamous cell carcinoma or adenocarcinoma were treated with chemoradiotherapy (4 cycles of 5-fluorouracil and cisplatin and radiotherapy (50 Gy at 2 Gy/d) or radiotherapy alone (64 Gy). The combined modality arm demonstrated a significant improvement in both median survival (14 vs. 9 months) and 5-year overall survival (27% vs. none) with projected 8-year and 10-year survival rates of 22% and 20% respectively.

Only a few studies described the toxicity results of the definitive chemoradiation for irresectable tumors (T4N0-1 M0). In a German study 22 patients were treated with induction chemotherapy with 5FU and cisplatin followed by concurrent chemoradiation therapy for T4 and obstructing T3 squamous cell carcinoma of the upper and midthoracic esophagus. A partial or complete response was seen in 9 (41%) and 1 (5%) patients, respectively, and 41% of the patients were alive at 2 years after treatment. The main toxicities in this cisplatin based chemoradiation scheme were leukocytopenias (23%) as well as thrombocytopenias (9%) grade III and IV. A total of 10 patients (45%) had grade III and IV dysphagia during chemoradiation (in 32% of the patients this was already preexistent) [9].

Given the favourable toxicity profile of chemoradiation with carboplatin and paclitaxel in the preoperative setting, a phase II study was performed in the Netherlands with concurrent chemoradiation with paclitaxel and carboplatin as definitive treatment for patients with irresectable esophageal cancer. Durable locoregional control and palliation was achieved in about half of the patients. Median overall and disease-free survival were 17 months and 9 months respectively [10]. The main grade 3–4 toxicities were neutropenia (16%) thrombocytopenia (4%), esophagitis (12%) and (fatigue (8%).

Since 2003 patients with irresectable esophageal cancer as well as patients medically unfit for surgery, but deemed fit for definitive chemoradiation were treated in our centre with this treatment scheme. The tolerability of this chemoradiation treatment regimen for medically inoperable patients has never been described in a substantial cohort of patients.

Therefore, in this retrospective cohort study we compare acute toxicity of the definitive chemoradiation with carboplatin and paclitaxel in patients with medically inoperable esophageal cancer and patients with irresectable esophageal cancer.

To our knowledge this is the largest retrospective study reporting on toxicity of definitive chemoradiation in patients with inoperable and irresectable esophageal cancer. We observed a significantly higher grade ≥ 3 toxicity in the patients that were medically inoperable compared to patients that were irresectable, resulting in significantly more hospital admissions and incomplete administration of chemotherapy.

Interestingly in our series the patients with inoperable esophageal carcinoma had a significantly shorter tumor length and consequently a smaller radiation field. Furthermore in the inoperable group 40% of the patients had low stage disease with stadium I-II disease. In despite of a smaller radiation field and lower tumor stage the observed toxicity was significantly higher.

In the literature a range of toxicity grade 3 or higher in definitive chemoradiation is observed from 11% to 50% of the patients depending on the proportion of patients with T4 disease [14‐17]. Of note, the majority of these studies used the 5FU cisplatin scheme for which the main observed toxicities were neutropenia, mucositis, diarrhoea and neuropathy [3, 10, 14, 15].

In order to complete the scheduled chemotherapy toxicity grade ≥ 3 should be minimized and hospital admission reduced. The most important reasons for the majority of hospital admissions were dehydration as a result of mucositis or esophagitis and neutropenic fever [16].

To prevent dehydration the start of enteric feeding in an early stage could be a feasible treatment option. Moreover, during chemotherapy administration, from cycle 5 onwards standard extra intravenous fluid suppletion could be considered. Finally, the introduction of prophylactic quinolones, starting from the fifth cycle, could be considered to prevent neutropenic fever in this patient population.

Failure after treatment of esophageal cancer in our series concerns both local recurrence and distant metastases in comparable frequencies without significant differences between inoperable patients and irresectable patients. The increased locoregional and distant recurrence rate (although not significant) in irresectable patients reflect the higher tumor stage in this group. Therefore, the lower toxicity in the irresectable patient cannot be explained by favourable tumor characteristics or smaller radiation field sizes. Half of the patients with distant failure have concurrent locoregional recurrence. This suggests that not only optimization in the administration of chemotherapy could be instrumental in the improvement of treatment outcome in patients with esophageal cancer receiving definitive chemoradiation, but also approaches aimed at reducing the risk of local relapse. For example, an esophagectomy after definitive chemoradiation or an integrated boost on the primary tumor could improve local control. These approaches are subject of ongoing Dutch studies. (NTR 3060, NTR3532).

Some limitations to our study should be noted. Data were retrospectively collected which may have resulted in an underestimation of toxicity occurrence. Furthermore, toxicity grade 1 and 2 were not scored in detail. The study reports on a single institute experience, which may not be representative of all practices that use the same chemoradiation scheme. Finally, the focus of this research was acute toxicity of definitive chemoradiation. Although survival between the two groups was not significantly different between the inoperable and irresectable group no definitive conclusions on survival can be drawn from this study.

This is the first large study reporting on grade 3–4 toxicity of definitive chemoradiation with carboplatin and paclitaxel in patients with inoperable or irresectable esophageal cancer. Our data show that toxicity is worse in the inoperable group compared to the irresectable group and mainly occurs in the 5th cycle of treatment. Therefore, improvement of supportive care should be undertaken in this more fragile group to minimize side effects, preventing incomplete administration of chemotherapy, and thereby possibly prolonging survival.