Early Palliative Care in Patients With Metastatic Upper Gastrointestinal Cancers Treated With First-line Chemotherapy

Medical oncology is aimed to increase patient's survival, even at metastatic stages, in addition to disease-related and treatment-related symptoms. However, providing palliative care (PC) which includes symptoms management, nutritional support, psychosocial support, as well as assistance on end-of-life preferences, may be as important as survival issues to improve quality of life in such setting. In France, PC has been traditionally offered late, at end-life stage, although the World Health Organization recommends providing PC as earlier as possible in the course of the disease, in order to increase quality of life.

Decades ago, PC services were initiated in France in order to provide a medical alternative to the use of questionable medical practices regarding the end of life period: abandonment, euthanasia, and inappropriate aggressive therapy. According to the French society of palliative care, PC is an approach aimed to provide active care, in a holistic approach, to the person with a serious, progressive or terminal illness. The objective of PC is to relieve pain and other distressing symptoms, but also to take into account the psychological, social and spiritual suffering. PC offers an interdisciplinary support system to help patients and their relatives. As mentioned previously, PC has been in France (but also in the US) usually offered late, at end-life stage. Actually, PC access became a Right guaranteed by the Law, for patients and their families in 1999. This context should explain why even nowadays, PC often means " end of life " not only for the lay-man for the general public but also for caregivers, and some doctors.

The last World Health Organization (WHO) recommendations are far less restrictive than the 1996 French recommendations, as it is stated that PC should be offered as earlier as possible in the course of the disease, in order to increase quality of life, and to positively influence the course of illness. The World Health Organization recommendations add that PC is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those investigations needed to better understand and manage distressing clinical complications.

In a recent randomized study, 151 patients with newly diagnosed metastatic non-small-cell lung cancer were randomized to receive either early PC (EPC) combined with standard oncologic care or standard oncologic care alone. It was hypothesized that patients, who received EPC, compared with patients who received standard oncologic care only, would have a better quality of life (primary endpoint). The first visit with the PC service set up within the first 12 weeks, and the median number of visits in the EPC group was 4. In this study, the authors referred to the recommendations of the National Consensus Project for Quality Palliative Care. Among patients with metastatic non-small-cell lung cancer, EPC led to significant improvements in quality of life. In addition, EPC led to significant improvements in mood, as well as in overall survival (median survival, 11.6 vs. 8.9 months; HR=0.60, p = 0.02)), despite less aggressive end-of-life care.

Following the publication of this American study, the American Society of Clinical Oncology recommends nowadays that "combined standard oncology care and PC should be considered earlier in the course of the illness for any patient with metastatic cancer….". However, it is clear that a gap exists (not only in France) between this recommendation and the current practice. In addition, there is no consensus on how early PC should be integrated in oncologic services, even though an underpowered small randomized trial reported recently an insignificant better survival favoring early versus delayed (3 months later) initiation of PC.

The results of the study described above, although formally restricted to the field of metastatic non-small-cell lung cancers, have modified the perception of many oncologists about the objectives of PC. However, additional clinical studies should be done before considering EPC as an additional survival input in other advanced malignancies.

The median survival of metastatic upper gastrointestinal (GI) cancers such as pancreatic cancers, gastric cancers, and biliary tract cancers did not exceed 10-11 months, which is as poor as reported with metastatic lung cancers. Standard of care in the metastatic setting in upper GI cancers are described in ad hoc French guidelines, i.e.: "Thésaurus National de Cancérologie Digestive". Briefly, standard of care in metastatic pancreatic cancer in the first-line setting lies on the combination of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX regimen) for patients without any cholestasis and in good performance status, and on gemcitabine monotherapy. In metastatic biliary tract cancers, standard of care lies on gemcitabine-based regimen (gemcitabine monotherapy, gemcitabine plus cisplatin, or gemcitabine plus fluorouracil). Besides HER2 positive metastatic gastric/gastrooesophageal patients who present with much better prognosis, and should be treated with trastuzumab-based regimen, most of patients with metastatic gastric/gastrooesophageal HER2 negative patients (IHC + or IHC ++ with negative fish/sish) have poor prognosis, with similar survival rates than patients with other upper GI malignancies. In that setting, several regimens may be offered to patients, such as the following: Folfox, EOX/ECX, Folfiri, LV5FU2-cisplatin, Capecitabine-platinum salt or docetaxel-based regimen ...). Several experimental treatments (antiangiogenics, met inhibitors, modulators of immune check points, etc...) are currently tested in metastatic gastric/gastrooesophageal cancers, but these treatments are restricted to patients in good health condition who accept to participate to clinical trials, and none of these trials have yet produced meaningful survival benefit in the first-line setting.

To summarize, therapeutic advances in the setting of metastatic upper GI cancers are infrequent, and often modest. Providing an extra survival benefit for these patients with EPC, may contribute to deeply modify the practice of care of oncology in France.

Inclusion criteria

• Patients with an upper gastrointestinal metastatic cancer: pancreatic, biliary tract, esophageal or gastric (including junctional Siewert 2 and 3 cancers) cancers.

NB: gastrooesophageal junctional cancers with dysphagia and/or gastric/gastrooesophageal cancers with unknown or positive HER2 status are not eligible.

• Patients planed to be treated with first-line chemotherapy for metastatic disease.
• Age ≥ 18 years
• Life expectancy ≥ 1 month
• Performance status (OMS) ≤ 2
• Good understanding of French language
• Signed and dated informed consent
• Patients covered by government health insurance

Exclusion criteria

• Locally advanced cancer
• Junctional Siewert 1 gastrooesophageal cancer
• Gastric or junctional gastrooesophageal cancer with dysphagia (Atkinson>2)
• Gastric or junctional gastrooesophageal cancer with unknown or positive HER2 status (IHC: +++ or IHC ++ and FISH/SISH +)
• Compression of the biliary tract requiring a bypass