Inclusion Criteria:

1. Age ≥18 years. 2. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A section 24). 3. Patients must have a malignancy that is metastatic or unresectable (for surgical or medical reasons). 4. Typical retroperitoneal pain syndrome (pain that radiates from the lower back to the upper abdomen, belt like distribution). 5. Uncontrolled pain at recruitment, defined as >=5 on 11 point BPI scale despite analgesic use. 6. Anatomical involvement of the celiac plexus, as defined by at least one of the following: 1. Any Pancreatic cancer. 2. Any other cancer that on imaging demonstrates either: gross involvement of the celiac blood vessels or celiac plexus on imaging OR haziness around the celiac blood vessels, that typically implies tumor engulfment. 7. Recent abdominal imaging (CT, PET or MRI) should be at most 2 months old. The CT simulation performed as part of the protocol will be considered sufficient. 8. Prior chemotherapy or biological treatment is allowed, but any active oncological treatment should be stopped at least 6 days prior to radiation and renewed at least 6 days following radiation. For trastuzumab emtansine a 14 break prior to, and a 6 day break post-therapy is required. Hormonal treatments (e.g. tamoxifen, androgen ablation, androgen antagonists, aromatase inhibitors), and bone-strengthening agents (e.g. bisphosphonates, anti-RANKL antibody denosumab) may be continued during the radiation treatment, and do not need to be interrupted. 9. Willingness to attend 3- and 6- week follow-up visits, and participate in telephone follow-up thereafter. 10. Radiation is known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of therapy. 11. Ability to understand and the willingness to sign a written informed consent document. 12. Before patient registration, written informed consent must be provided.

Exclusion Criteria:

1. Patients under 18 years of age. 2. Patients who are well balanced in terms of pain control. 3. Patients with life expectancy <8 weeks as defined by the primary oncologist. 4. Known serum albumin <2.4 (does not need to be especially tested if unknown).* 5. Known lymphopenia defined as <12% of white blood count (does not need to be especially tested if unknown).* 6. Altered mental status (defined as change in brain function from baseline including confusion, drowsiness, delirium, dementia or coma)* 7. Leptomeningeal spread* 8. Current or previous spinal cord compression* 9. Significant comorbidities (this is left to physicians' discretion. Guidance provided below section 8.4. As an example, patients with metastatic cancer, in the context of combined impaired renal and hepatic function are expected to have a poor survival)* 10. Patients with ECOG Performance status 3 or 4* 11. Any concurrent chemotherapy or biologic treatment is prohibited during 1 week before until 1 week following radiotherapy. 12. Previous radiotherapy to upper abdomen. 13. Conditions associated with increased side effects to radiotherapy (Inflammatory bowel disease, scleroderma for example). 14. Patients who have not recovered from the acute adverse events due to prior anti-cancer therapy (however peripheral neuropathy and other chronic side effects of anti-cancer therapy are not exclusion criteria). 15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. 16. Special populations: pregnant women, prisoners, patients with major psychiatric illnesses. 17. Unwilling or unable to attend 3-week and 6-week post treatment assessments.

• - these factors are all associated with a very poor prognosis.

40 ------ Nb There are criteria that exclude patients from performing the six-minute walk test (see section 29). These patients may nonetheless participate in the protocol and undergo celiac axis radiosurgery.

Severe lower back pain radiating anteriorly in a belt-like distribution is characteristic of pancreatic cancer. The pain is thought related to involvement of the celiac nerve plexus, located behind the pancreas; due to either macroscopic compression or microscopic perineural invasion. Contemporary approaches (narcotic analgesics, celiac nerve blocks and systemic chemotherapy) each have drawbacks, and as a consequence many patients suffer from severe pain. We hypothesized that ablative radiosurgery (high dose, precise X-ray treatment) focused on the celiac plexus would succeed in palliating these patients, possibly by interrupting pain transmission. It is important to emphasize that bringing pain relief to cancer patients is not only humane, but also associated with improved mood, quality of life and possibly improved survival. Our preliminary results suggest that the treatment is both effective and well tolerated; furthermore it appears that the patients tolerate subsequent cytotoxic treatments better. We will perform a prospective phase II multicenter clinical trial to test our hypothesis Compared to the small pilot trial the follow-up trial will: 1) Enroll a larger number of patients (n=100). 2) Be performed across a number of institutions, in both the Middle East and the United States. 3) Include improved measures of quality of life and functional capacity. 'Caregiver burden' and 'Patient hope' will also be assessed. 4) Incorporate exploratory translational endpoints relating to immune activation. Target population Adult patients with severe, poorly controlled lower back/abdominal pain (intensity at least 5/10 on the Numeric Pain Rating Scale) thought to originate in the celiac plexus (generally, but not exclusively, from pancreatic cancer). Patients with a poor prognosis, and those with previous radiation to the upper abdomen will be excluded. Systemic therapies will need to be stopped several days prior to, and following, treatment.

Arms

Experimental: celiac radiosurgery, single fraction

Celiac Plexus Radiosurgery

Interventions

Radiation: - Celiac Plexus Radiosurgery

patients will receive a single radiation treatment of 25 Gy directed towards the celiac surgery, and at the physician's discretion also abutting tumor