Keywords

Adenocarcinoma of the esophagus and gastro-esophageal junction is a highly aggressive and deadly disease. In Western countries, the incidence is rising and has already surpassed the numbers of squamous cell carcinoma in some areas [1]. In a population-based study less than 50% of patients were eligible for surgical treatment (42% received esophageal resection) [2]. Therefore, more than 50% of patients are in palliative setting. This number increases over time, since patients with recurrent disease or incomplete resection most likely will enter palliative treatment with developing efficacy. The group of patients not qualifying for curative surgical resection comprises of those with locally advanced unresectable tumors (T4 invading neighboring organs, predominantly trachea, heart, vessels), distant metastatic disease, carcinosis, and individuals, who deny surgery or suffer on severe comorbidities. The most frequent problem, we have to deal with, is dysphagia (Table 13.1), which finally can lead to complete disability to swallow, malnutrition, loss of body weight, aspiration, and of course to a massive reduction of quality of life. Weight loss of more than 10% worsens the prognosis, in particular this concerns advanced cases. Other tumor-related complications are pain, bleeding, and fistulation, either to the tracheobronchial tree and/or mediastinum (Figs. 13.1 and 13.2). A variety of therapeutic approaches are used, especially to alleviate dysphagia [4], but there is no single “best treatment option” existing, so therapeutic alternatives have to be discussed with the patient and adapted to his/her needs as well to PS. In a survey with 55 gastric and GEJ cancer patients, under palliative CT ability of self-care and tolerability of therapy were rated highest in importance [5]. So patients’ view is not necessarily in congruence with specialists’ opinion. Palliative therapy needs a multimodal and multidisciplinary approach and should be reviewed in an oncological tumor conference.

Table 13.1 Dysphagia score (Mellow and Pinkas [3]) to assess therapeutic efficacy
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Fig. 13.1
figure 1

CT scan of a patient with esophageal cancer, showing the spacious and devastating distribution of the contrast media within the mediastinum caused by a tracheo-esophageal/mediastinal fistulation

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Fig. 13.2
figure 2

Effect of stenting on a tracheoesophageal fistula. (a) Depicts a residual leakage (arrow) after a tracheal stent (Leufen aerstent® TBS, fully covered, 16/40 mm) was placed. (b) An additional esophageal stent (Niti-S™ Esophageal Stent, fully covered, 18/100 mm) was implanted, which led to a separation of the esophageal and tracheal compartment, preventing aspiration

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Extracting data and further more drawing conclusions for options of palliative treatment have to be done very carefully. This is mainly due to different design of the studies. Prognosis in patients on palliative track seems mainly dependent on possibilities to apply antitumor therapy [6]. Knowledge of prognostic factors (e.g., weight loss, PS, ability to swallow, pain) will help to determine the right choice of therapy [7]. Clinical outcome and patient-related outcome are not necessarily linked together. Surprisingly, as example, DCF compared to CF gives better results of HRQoL, although DCF is accompanied by higher toxicity [8]. One possible explanation for this unexpected finding is that more aggressive therapy might increase patient’s hope and tolerance.

13.1 Palliative Chemotherapy

Adenocarcinoma of the esophagus and GEJ is assumed to have a very similar profile as gastric cancer [9] and therefore frequently dealt together. Restrictively it must be admitted that differences seem to exist [10].

There is consensus that a CT should be offered to patients with incurable tumors and physical fitness [11]. The goal is to extend survival time [10], improve/maintain HRQoL, and restore/maintain organ function. This benefit is questioned for individuals with reduced PS. There is some ongoing debate, whether CT is able to improve or just slow down deterioration of HRQoL [12]. It is still a controversy, which combination and substances should be applied, and also guidelines with slightly different recommendations exist. Most used chemotherapeutic regimens are based on combination of cisplatin and 5-FU. A randomized study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin confirmed noninferiority. PFS and RR were comparable, and median survival was ECF: 9.9 months, ECX: 9.9 months, EOF: 9.3 months, and EOX: 11.2 months with a HR for death of 0.8 for EOX over ECF. Toxicity was similar for fluorouracil and capecitabine, whereas oxaliplatin caused more neuropathy and less renal toxicity [13]. If a standard of care is combination of platins and fluoropyrimidines, expanding this to a triplet with docetaxel achieves better results (DCF vs. CF, ORR: 37% vs. 25%; median TTP 5.6 vs. 3.7 months; MOS: 9.2 vs. 8.6 months) [14, 15], although having to pay the toll of higher hematologic toxicity (Neutropenia Grade 3–4: 82% vs. 57%). DCF-treated patients also had better HRQoL [16] and clinical benefit in terms of maintaining PS and body weight. There was no measurable impact on pain or opioid need [17].

Various modifications have been developed, searching for better tolerability than the DCF regimen, e.g., FLOT [18] or adding G-CSF [19]. Since capecitabine was found to be equal to 5-FU [13], most patients, if possible, prefer oral administration and furthermore implantation of a venous access device can be avoided or at least delayed. A meta-analysis including almost 3500 patients, searching for optimal first-line CT demonstrated an advantage of triplet over doublet CT (OS: HR 0.90; PFS: HR 0.80; objective response rate risk ratio: 1:25). In contrast, risk of thrombocytopenia, mucositis, and infection increased [16]. No statistical significance was found with adding anthracycline to a doublet. This contrasts with Wagner’s publications [20, 21], whereas all other results mainly conform.

After failure of first-line therapy, the COUGAR-02 trial proved the efficacy of second-line monotherapy with docetaxel versus BSC. MOS was found 5.2 versus 3.6 months as well as reduced dysphagia and pain [22]. In a comparison between irinotecan and paclitaxel, no relevant differences were detected, so both can be applied as second-line therapy [23]. Reliable data to second-line CT are still scarce and it remains an individual therapeutic decision depending on patient’s preference and PS [24].

In a recently published Cochrane review, it has been shown with high quality of evidence that in palliative setting CT and/or TT increase OS (MOS: 6.7 vs. 5.7 months, HR 0.75), furthermore adding only TT improved also PFS (HR 0.64, moderate quality of evidence). These therapies seem to increase toxicity grade ≥3, whereas there was no clear proof for increased treatment-related mortality. Only very low evidence was found in a small sample for the improvement of HRQoL [10].

13.2 Targeted Therapy

The ToGA [25] trial investigated the efficacy of adding trastuzumab to a CT, targeting human epidermal growth factor receptor 2. It showed an increased MOS of 13.8 over 11.1 months in HER2 positive tumors. So, a HER2 status should be determined for selecting cases, which will benefit from adding trastuzumab. Trastuzumab should not be administered with anthracycline simultaneously.

A further promising antibody is ramucirumab, which acts against VEGFR2, blocking angiogenesis. A significant better survival was shown in the REGARD [26] trial (Ramucirumab vs. BSC, 5.2 vs. 3.8 months) and RAINBOW [27] study (paclitaxel plus ramucirumab vs. paclitaxel monotherapy, 9.6 vs. 7.4 months). Ramucirumab was also proven to increase OS and PFS in patients previously treated with chemotherapeutic agents [10]. Other tested monoclonal antibodies and tyrosinkinase inhibitors did not show high antitumor effects, and a study directed against hepatocyte growth factor receptor (MET) was interrupted due to high mortality in the treatment group [28, 29].

Taken together, application of targeted therapies increases MOS and even PFS in palliative setting. It is still somehow open, from which patient profile benefits the most.

13.3 Palliative Radiotherapy and Chemoradiotherapy

Radiotherapy definitely plays a role in the therapeutic spectrum of esophageal cancer. It is a valid alternative/addition for palliation. There is a reasonable effect reported on symptom control, particularly dysphagia. This can be accomplished by EBRT or BT and also by combination of both or other measures of recanalization of the esophagus. New techniques in planning and delivery of radiation are expected to allow higher precision in targeting the tumor and therefore reducing damage to surrounding healthy tissue [30]. Probably RT, stent placement, or a combined management of both are mostly applied. Two randomized studies [31, 32] compared BT with stent placement, and the bottom line was that initially stents are more effective, whereas the esophageal patency of BT lasts longer [33], latter is in line with HRQoL [34]. Complications were less in the BT group (21% vs. 33% [31] or 13% vs. 25% [34]). Stenting appears very appropriate in patients probably expecting short survival. In a further randomized trial, increasing evidence emerges supporting the combination of SEMS and BT [35] as a very efficient method. Adding EBRT (30 Gy/10 fractions) to high-dose-rate BT (8 Gy/2 fractions 1 week) proved superiority to BT alone in a randomized study. This affects dysphagia, odynophagia, regurgitation, pain, PS, and HRQoL, whereas MOS and severe adverse events did not differ [36, 37]. The efficacy and safety of BT are reviewed in a recent meta-analysis [38] with resolution of symptoms in 87% after one month, a low mortality rate of 0.3%, and adverse effects of 23.4%. A more frequent use of BT is advocated, but it must be admitted that availability of BT is not everywhere.

A comparison between CRT (50 Gy) and RT alone (64 Gy) clearly demonstrated an advantage in favor of CRT (MOS 14.1 vs. 6.3 months) [39]. These results also get supported by a retrospective study comparing survival of SEMS versus CT versus RT versus CRT with MOS of 6.92, 7.75, 8.56, and 13.53, respectively. The only independent predictor in the multivariate analysis was the treatment modality [40]. Similar supporting results were obtained by a review primarily focusing on patient-related outcome [8].

13.4 Stenting

Introduction and continuous further development of expandable stents have brought a big advancement in treating dysphagia. Easy handling during placement, better results, and less complications led to a nearly complete replacement of the older plastic tubes. Such tubes were associated with high clinical mortality (>10%) and complication rate [41, 42]. There are many expandable stent models offered, made either of an alloy of nickel and titan or steel or plastic (SEPS). The use of SEPS is highly decreased because of a higher migration rate and therefore need of further interventions. At the time being, SEMS are mostly used, fully or partially covered with synthetic covering—to prevent tumor ingrowth, with or without a reflux valve. Double-layered (second external metal mesh around a covered stent) is expected to reduce migration. Alternatively, biodegradable models are available, which in first-line seem more appropriate for benign diseases. To discuss different brands of stents goes beyond the scope of this chapter due to different availability, variety and rapid change in design and technical aspects. Selection of the most appropriate stent has to be done depending on the tumor location, size, configuration, and length of stenosis [43]. Placement is performed endoscopically or radiologically in sedoanalgesia or in general anesthesia, in selected cases with expected difficult stent placement or high risk of aspiration. Typical complications in the early phase are perforation, aspiration, pneumonia, pain, migration, and reflux. Late complications are migration, recurrent dysphagia due to tumor in- and overgrowth, food impaction, bleeding, formation of an esophageal fistulation, particularly to the airways, migration, perforation, and reflux. Stents placed over the GEJ form an open channel allowing reflux of gastric juice. To overcome this problem, stents with integrated reflux valves were introduced. The value of these is not clearly defined [44] and has to be compared with PPI administration. Although stents provide a rather rapid relief of dysphagia, the disadvantage is recurrent dysphagia within a few weeks. So, it appears reasonable to combine stent with BT notably for patients with estimated longer life span [31]. Feasibility and safety of this additive treatment have been shown, although a substantial increase of HRQoL except relieving dysphagia was not observed [45, 46]. Further promising results are expected with SEMS covered with 125I seeds providing prolonged survival compared to covered SEMS (MOS 177 days vs. 147 days) with comparable side effects [47].

13.5 Other Palliative Treatment for Alleviation of Dysphagia

Different further measures are used to achieve relief from dysphagia. Thermal and chemical methods are locally applied like laser, photodynamic therapy, argon plasma coagulation, and injection of ethanol. Probably APC is the most used thermoablative method, which seems technically easier to apply with a reduced risk of perforation compared to laser [48]. In a randomized comparison of APC alone to a combination with either BT or PDT, a longer dysphagia-free period was observed for combined modalities, whereas these did not differ from each other. As well less complication as better HRQoL was shown in the APC-BT group [49]. In addition, availability of laser and PDT is limited and also requires specialized experience. Photosensitization of the skin and a distinct danger of perforation as side effects of PDT also must be taken into account [50].

In a meta-analysis, comparing the outcome between SEMS and other locoregional palliative treatment methods, stents needed less recurrent interventions, whereas a survival advantage was observed for the others [44]. So, recanalization with other methods apart from SEMS are mainly used, if stents cannot be placed, e.g., in situation where the tumor is very close to the upper esophageal sphincter.

Mechanical dilation can be applied as an adjunct to widen the esophageal lumen before inserting a stent. The sole use of dilation is only recommended for selected cases with poor prognosis.

13.6 Role of Surgery

Besides attempts of rescue surgery, mainly due to perforation or bleeding, nearly all of palliative surgery and bypasses became obsolete because of high rates of morbidity (30–70%) and mortality (20–40% in the literature) [53,54,53]. This in turn leads to prolonged hospital stay and reduced HRQoL.

Nevertheless, some reports advocate palliative resection. Independent prognostic variables, which lead to poor survival, were identified as local or diffuse peritoneal carcinosis, solid organ matastases, signet cell histology, ASA III–IV, and advanced tumor stage [54]. This management applies only for a very small and highly selected group of patients. And it has to be noted that this study mainly focuses on OS but not on HRQoL.

One has also to bear in mind that development of new drugs, targeted therapies, and radiation techniques might offer new therapeutic approaches [55]. So, the border of unresectability might shift towards potential radical resectability due to downsizing and/or downstaging of the tumor. This could affect locally advanced tumors as well as metastatic ones in selected cases. The role of ablative therapy of metastases needs still to be defined.

13.7 General Supportive Measures

Pain medication, psychooncological support, and if required social help must be offered to patients with esophageal cancer. This should help these individuals to alleviate problems induced by this heavily aggressive disease. Nutritional status plays a major role and it has been shown that it is predictive for the course of the disease [56]. In some cases, a PEG tube is required, where oral intake cannot be achieved with other measures. This mainly applies for tumors highly located.

13.8 Conclusion

Palliative therapy of esophageal cancer has to be adapted to PS, concomitant diseases, organ function, morphology, and complications of the tumor. It should minimize the requirement for multiple therapeutic sessions and of course be in concordance to needs and wishes of the patient. This therapy is based on the concept of multimodality and multidisciplinarity. If PS is good, a systemic CT and/or TT should be offered. This increases OS and has some positive effect on PFS and HRQoL. If first-line CT fails, a second-line CT and/or TT should be pursued. Oral food intake needs also to be restored. In case of reduced PS patency of the esophageal canal (e.g., stent/BT) and BSC are the foremost aim of palliation, providing the highest possible level of HRQoL. In some selected cases, a reduced systemic therapy might be appropriate.

13.9 Final Remark

This chapter was also crosschecked with selected published guidelines [11, 59,60,61,62,61].