Immunotherapy and Imaging of Metastatic Pancreatic Adenocarcinoma

Metastatic Pancreatic Adenocarcinoma

Pancreatic adenocarcinoma is one of the most lethal types of cancer. In the United States, it has become the fourth leading cause of cancer-related death in men and women and it remains one of the cancers most resistant to traditional therapies.

At present, the only curative treatment for pancreatic cancer is complete surgical resection. For patients with localized disease confined to the pancreas without extra-pancreatic extension or lymph node metastases, complete surgical resection can yield 5 year survival rates of 18-24%. However, a large number of pancreatic cancers are locally advanced or are metastatic at the time of diagnosis. As such, fewer than 20% of patients are candidates for surgery and require systemic therapy.

With the emerging understanding and application of cancer immunotherapy, several active and passive immunotherapy agents, either used individually or in combination, have shown promising results in clinical trials in treating metastatic pancreatic adenocarcinoma.

Medical Imaging

Medical imaging is fundamental in the evaluation of pancreat- ic adenocarcinoma and in assessing treatment response to immunotherapy. Primary imaging modalities employed in the evaluation of pancreatic cancer following immunotherapy include contrast-enhanced computed tomography (CT), contrast-enhanced magnetic resonance imaging (MRI) and F18 positron emission tomography coupled with computed tomography (F18-FDG PET/CT).

Computed Tomography

Computed Tomography (CT) with intravenous contrast is the imaging modality of choice for the diagnosis and staging of pancreatic carcinoma as well as for monitoring its response to immunotherapy. CT enables visualization of the primary tumor as well as the adjacent vasculature while simultane- ously providing an assessment of local and distal disease spread.

With CT imaging, pancreatic carcinoma appears as a hypoat- tenuating mass which gradually enhances with delayed imag- ing. Approximately 10% of tumors can be isoattenuating to the surrounding normal parenchyma thereby leading to misdiagnosis. Indirect signs such as upstream pancreatic ductal dilatation with abrupt cut off, atrophy of upstream parenchyma and biliary dilatation are considered to be indicators of tumors when a mass is not clearly identified on CT.

Over and above the primary diagnosis, CT allows characteri- zation of the tumor as resectable or unresectable by evaluat- ing the local extent and invasion, length and degree of involvement of adjacent vasculature and detection of lymph- adenopathy and other metastases.

MRI

Magnetic Resonance Imaging (MRI) performed with intrave- nous administration of gadolinium can be used for evaluation of pancreatic cancer in patients with equivocal findings on CT. MRI may also be used for characterization of liver lesions suspicious for pancreatic metastasis. Diffusion weighted MRI may be helpful in detecting small tumors and metastasis. MRI performed with gadoxetic acid contrast agents increases the sensitivity of detecting pancreatic liver metastasis to 85% versus 69% with CT.

FDG-PET/CT

Positron emission tomography (PET)/CT with FDG relies upon functional activity to differentiate metabolically active tumors from benign lesions. High-quality CT, however, is superior to FDG-PET/CT in the assessment of local tumor resectability. Some studies suggest that PET is useful for identifying metas- tasis missed by CT, while others have reported false-negative PET results with small tumors. Combined contrast-enhanced FDG-PET/CT can be utilized to provide comprehensive evalua- tion.

As PET can differentiate between post treatment necrosis/fi- brosis and viable tumor, FDG-PET is more sensitive than CT in assessing response to treatment following chemotherapy or radiation. FDG-PET is also more sensitive in detecting disease progression by tumor recurrence after resection as well as detecting subtle new metastatic disease. It has been demon- strated that standard uptake values (SUVs) on FDG-PET can be utilized as an independent prognostic factor of expression of tumor growth and tumor biologic behavior. Tumors with distant metastasis have higher SUV level than tumors without metastases and ultimately demonstrate a shorter survival. In addition, a higher metabolic activity at baseline in the primary tumor in patients with resectable disease has found to show better response to neoadjuvant chemotherapy.

Immune-related Response Evaluation Criteria In Solid Tumors – irRECIST

Treatment response of pancreatic carcinomas that are treat- ed with traditional chemotherapy, radiation therapy, or surgi- cal resection, may be evaluated using conventional methodol- ogies. The most commonly utilized methodology is the

Response Evaluation Criteria in Solid Tumors (RECIST) criteria. By RECIST criteria, early tumor growth or the appear- ance of new lesions is definitively considered progressive disease and thereby a treatment failure.

However, in recent clinical trials studying cancer immuno- therapies, it has been demonstrated that unlike conventional cytotoxic chemotherapy, tumors treated with immunothera- py demonstrate a delayed response to treatment. In fact, though there is eventual tumor shrinkage with clinically significant long-term tumor-size stability, often transient enlargement of tumors or appearance of new tumors is encountered. As a result of this delayed response, the utiliza- tion of RECIST criteria is problematic as it leads to incorrect classifications as progressive disease.

The understanding of these new patterns of treatment response after immunotherapy has thus resulted in the development of the Immune-related Response Evaluation Criteria In Solid Tumors (irRECIST). The utilization of irRECIST to assess immunotherapy treatment of metastatic pancreatic carcinoma avoids premature termination of otherwise effec- tive immunotherapeutic treatments and makes therapy assessment more robust and reproducible.

Conclusion

The development of immunotherapy along with more traditional treatment strategies has resulted in an opportuni- ty to develop combination regimens for specifically targeted and optimal therapies. This combined methodology has already shown enhanced objective response rates in patients with melanoma suggesting that combination therapy is an important area for future investigation in other types of cancers. Pancreatic adenocarcinoma, due to its lethal nature, is an excellent area of development, however, the evaluation of response is challenging.

For Sponsors, these novel therapies demands expertise to implement imaging assessment criteria that provide an accurate evaluation of response given the changes in tumor biology. The development and implementation of these new criteria, however, can lead to more meaningful and reproduc- ible results and thus their use is paramount in executing successful trials.

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Volume 5, Issue 1: Guidance For Sponsors: Immunotherapy and Imaging of Metastatic Pancreatic Adenocarcinoma

Originally written by legacy Intrinsic Imaging Medical Director