"If cancer is the emperor of all maladies, then pancreatic adenocarcinoma is the ruthless dictator of all cancers," according to recent editorial (JAMA. 2016;315:1837-1838).
Now the American Society of Clinical Oncology (ASCO) has issued a series of guidelines on the management of all stages of this doleful malignancy.
Even potentially curable pancreatic cancer — which represents only about 20% of all patients — has a 5-year overall survival rate of 25% to 30% at best, note the guidelines authors, headed by Alok Khorana, MD, from the Cleveland Clinic.
"This disease is an unfortunate exception to the general trend of improvement in cancer-related mortality," Dr Khorana observed.
"Indeed, one estimate suggests that pancreatic cancer will become the second leading cause of cancer-related death in the United States within the next decade," he added.
With this as a sobering background, ASCO experts have issued a series of recommendations for the management of pancreatic cancer tailored to the stage of the disease.
Guidelines on the management of potentially curable, locally advanced unresectable, and metastaticpancreatic cancer were published online May 31 in the Journal of Clinical Oncology.
Potentially Curable Pancreatic Cancer
For patients with potentially curable pancreatic cancer, the experts recommend that, after histopathologic confirmation of the diagnosis, clinicians should perform a multiphase CT scan of the abdomen and pelvis using a pancreatic protocol or MRI to gauge the anatomic relations of the tumor to other internal structures and to evaluate patients for the presence of intra-abdominal metastases.
In this patient group, supplemental studies might include endoscopic ultrasound, diagnostic laparoscopy, or both.
A patient's performance status, symptom burden, and comorbidity profile should be carefully evaluated at baseline, and the goals of care should be shaped by what patients want before arriving at a multidisciplinary treatment plan.
Patients also need to be informed about any relevant clinical trials for experimental or palliative care.
Perhaps the most important question clinicians must address for patients with potentially curable disease is who should be offered primary tumor resection.
Appropriate candidates for primary tumor and regional lymph node resection should meet the following criteria:
Some patients with potentially curable pancreatic cancer may do better if they undergo preoperative therapy followed by primary tumor resection, Dr Khorana and his colleagues indicate
Patients who might benefit from preoperative therapy include those in whom radiographic findings are suspicious but not diagnostic for extrapancreatic disease.
Similarly, patients with a poor performance status or comorbidities not conducive to major abdominal surgery might be considered for preoperative therapy if it is thought that their status might be reversed after treatment.
Candidates for preoperative therapy can also include those who have a radiographic interface between the primary tumor and mesenteric vasculature or those whose CA 19-9 levels are suggestive of disseminated disease.
The ASCO authors caution, however, that after preoperative treatment, patients need to be completely restaged before making plans for surgery.
What about patients who go directly to primary tumor resection?
"All patients with resected pancreatic cancer who did not receive preoperative therapy should be offered 6 months of adjuvant chemotherapy with either gemcitabine or fluorouracil plus folinic acid in the absence of medical or surgical contraindications," Dr Khorana and his colleagues state.
Treatment should be initiated in the 8 weeks after surgery (assuming full recovery).
The authors also recommend that patients who have not received preoperative therapy and who have microscopically positive margins or node-positive disease after 4 to 6 months of adjuvant chemotherapy be offered adjuvant chemoradiation.
Although evidence supporting the duration of preoperative therapy is weak, the panel recommends that patients receive a total of 6 months of adjuvant therapy, including time spent on the preoperative regimen.
Patients might also need ongoing supportive care for symptoms that result from the treatment itself, and they should be followed every 3 to 6 months after completion of their treatment course.
Locally Advanced Pancreatic Cancer
More than half of all patients with pancreatic cancer have locally advanced unresectable disease.
"This group of patients can be challenging to treat, because they generally have problems related to their local tumor burden before developing metastatic disease," lead author Edward Balaban, MD, from the Penn State Hershey Cancer Institute, and his colleagues write.
Local disease control and quality of life are the important issues in this patient population, they add.
With an expected 5-year overall survival rate of less than 5%, recommendations for the management of locally advanced pancreatic (LAPC) are more limited than they are for potentially curable disease.
The authors again recommend that clinicians use multiple CT scans to assess disease extent in the chest, abdomen, and pelvis, but they do not recommend the use of other staging studies on a routine basis.
Patients should also be assessed for baseline performance status, symptom burden, and comorbidities, and clinicians again need to discuss the goals of treatment in collaboration with a multidisciplinary team shaped by patient preferences.
LAPC patients should also be informed about any relevant clinical trials for which they might be eligible.
In contrast to potentially resectable pancreatic cancer, initial treatment for LAPC should include some form of combination regimen for individuals who have a performance status of 0 or 1, who have a favorable comorbidity profile, and who want to and are able to undergo an aggressive medical regimen.
"There is no clear evidence to support one regimen over another," Dr Balaban and his colleagues note. "And physicians may offer therapy on the basis of extrapolation from data derived from studies in the metastatic setting."
Chemoradiotherapy (CRT) or stereotactic body radiotherapy (SBRT) may be offered to patients with local progression but no metastases, provided they have a performance status of 2 or less and a favorable comorbidity profile.
"CRT may [also] be offered to patients who have responded to an initial 6 months of chemotherapy or have stable disease, have developed unacceptable chemotherapy-related toxicities, or [who] show a decline in PS as a consequences of chemotherapy toxicity," Dr Balaban and his colleagues recommend.
In contrast, if patients respond to CRT or their disease has at least stabilized after 6 months of induction CRT, "CRT may be offered as an alternative to continuing chemotherapy alone for any patient with LAPC," they add.
The authors indicate that patients with LAPC can be offered SBRT even though evidence supporting SBRT is not robust.
On completion of treatment, LAPC patients whose disease has stabilized or who have no disease progression should have a follow-up visit every 2 to 3 months in which they undergo liver and renal function tests.
They should also be tested for CA 19-9 levels and undergo CT scans at least every 3 months in the first 2 years after completion of treatment, and every 6 months if disease remains stable.
Finally, any patient who does not benefit from first-line treatment recommendations and who progresses despite clinicians' best efforts should be treated according to the ASCO guidelines for the treatment of metastatic pancreatic cancer.
These patients will also very likely need aggressive management of pain and other symptoms related to either the cancer or the therapy.
Symptom management, for example, might include a short course of palliative radiotherapy for those who have abdominal pain, worsening jaundice, or other prominent local symptoms.
Metastatic Pancreatic Cancer
For patients with metastatic pancreatic cancer, median life expectancy is less than 1 year, and the 5-year overall survival rate is only 2%.
"The clinical course of pancreatic cancer usually is aggressive, with high symptom burden and potential for a substantial deterioration in quality of life," write lead author Davendra Sohal, MD, from the Cleveland Clinic, and his colleagues.
Given these odds, "the goals of care (which include a discussion of an advance directive), patient preferences, and support systems should be discussed with every patient with metastatic pancreatic cancer and his or her caregivers," the authors suggest.
As for other stages of the disease, clinicians need to, again, assess disease extent in the chest, abdomen, and pelvis using a multiphase CT scanning.
Symptom burden and comorbidities also need to be assessed at baseline, and performance status noted.
As for early-stage disease, clinicians need to develop a treatment plan with the help of a multidisciplinary team and patient input, and every patient needs to know if there are relevant clinical trials in which they might participate.
Recommended first-line treatment for metastatic pancreatic cancer is the so-called FOLFIRINOX regimen, which consists of leucovorin, fluorouracil, irinotecan, and oxaliplatin. This protocol can be offered to anyone with a performance status of 0 or 1 and a favorable comorbidity profile who wants to and is able to withstand an aggressive medical regimen.
The FOLFIRINOX regimen also requires that patients have a chemotherapy port and access to infusion pump services.
Alternatively, patients who meet the same eligibility criteria can be treated with gemcitabine plus nanoparticle albumin-bound (NAB)-paclitaxel.
For those with more advanced disease (performance status, 2) or who cannot tolerate a more aggressive regimen but who still wish to received cancer-directed therapy, gemcitabine can be given alone or together with either capecitabine or erlotinib
In contrast, cancer-directed therapy should only be offered on a case-by-case basis to patients with a performance status of 3 or higher whose comorbid conditions are poorly controlled despite best efforts.
For patients who experience either disease progression on first-line therapy or intolerable toxicity, gemcitabine plus NAB-paclitaxel may be used as second-line therapy, provided patients want and can tolerate aggressive medical treatment.
Alternatively, fluorouracil plus oxaliplatin, irinotecan, or nanoliposomal irinotecan can be given as second-line therapy if patients have already received gemcitabine plus NAB-paclitaxel and want to and are able to withstand an aggressive treatment protocol.
For those who cannot tolerate aggressive therapy, clinicians can offer either gemcitabine or fluorouracil as a second-line option.
As with LAPC patients, patients with metastatic pancreatic cancer should be offered aggressive treatment to control pain and other symptoms related to the cancer or the treatment, the mainstay of which are opiate medications for pain.
"Physicians must address the level of pain and the degree of pain relief from analgesics at every clinical visit," the authors stress.
If patients are on cancer-directed therapy, they should undergo imaging — preferably CT scan with contrast — to assess first response to treatment 2 to 3 months after treatment initiation.
However, there are no data to establish how long cancer-directed therapy should continue or whether a third-line treatment should be used in this setting.
"Providing realistic hope to people diagnosed with pancreatic cancer, even though the prognosis may not be good, is important," Dr Khorana and his colleagues write.
"Patients deserve to know that their medical team is working to help them reach their goals," they add. "Even if cure is not possible, hope for an extension of life or good quality of life can be meaningful for people."
Dr Khorana reports serving as a consultant or in an advisory role for Eli Lilly, and has received research funding from Eli Lilly, ImClone Systems, Gilead Sciences, Merck, and Berg. Dr Balaban reports serving as a consultant or in an advisory role for Truven Health Analytics. Dr Sohal reports receiving research funding from Novartis, Celgene, OncoMed, and Beyer.
J Clin Oncol. Published online May 31, 2016
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