The Emerging Role of Neoadjuvant Therapy for Cancer of Pancreas

During our recent visit to Johns Hopkins Hospital, Baltimore, USA, for robotic pancreatic surgery, we had the opportunity to meet legendary Prof John L Cameron  (https://www.hopkinsmedicine.org/news/publications/hopkins_medicine_magazine/features/spring-summer-2017/the-cameron-factor). During a very lively and informative interaction, we were pleasantly surprised to learn that he was very well informed about India and had also visited as a tourist many places including Varanasi.

www.gicancerindia.com

Drawing from unmatched personal and institutional experience, Prof Cameron provided valuable insights into changing paradigms in the management of pancreatic cancer.

Neoadjuvant therapy and its likely impact on future management of pancreatic cancer was one such important topic that was discussed.

In the subsequent sections, we summarize the current literature on the subject in a simplified manner.

1.      What is Neoadjuvant therapy (NT)?  

Neoadjuvant therapy comprises of administration of chemotherapy alone or in combination with radiotherapy prior to curative surgery (surgery with an intention for cure) for cancer.

2.      Who are the candidates?

Currently NT is offered to patients who are diagnosed with 'Borderline Resectable Pancreatic Cancer (BRPC)' or 'Locally Advanced Pancreatic Cancer (LAPC)' following MDCT evaluation (angiography with < 3 mm axial sections utilizing dual phase pancreratic protocol).

Pancreatic cancer is defined as BRPC or LAPC if involvement of surrounding vascular structures precludes primary (upfront) resection. Approximately 30% of pancreatic cancer patients are identified as BRPC or LAPC.

3.      What are the objectives?

The only available current therapy that can provide long-term cure for pancreatic cancer is surgery with tumor free resection margin of > 1 mm (R0 resection).

The objective of NT is to downstage the local disease (i.e. reduction in the size of the local tumor) in patients with BRPC and LAPC so as to achieve R0 resection. Thus it offers possibility of curative surgery for this large group of patients who until now ended up with either margin positive (non curative) resection or were deemed inoperable.

Additionally NT may help eliminate undetectable micro-metastases thereby increasing probability of long term survival.

4.      What are the current NT protocols?

Briefly, current NT protocols involve either gemcitabine based chemotherapy (gemcitabine /nab-paclitaxel) or chemotherapy with FOLFIRINOX (5 FU, leucovorin, oxaliplatin and Irinotecan) and radiation as either conventional external beam therapy or stereotactic body radiation therapy (SBRT).

The detailed institutional protocols including duration, side effects etc can be accessed through the references provided at the end.

5.      How is the response to NT assessed?

Response to therapy can be assessed through estimation of serum CA 19-9 (pancreatic cancer tumor marker), pancreatic protocol CT scan and PET – CT scan performed before, during and after completion of NT.

A cut off value of CA 19-9 that can predict response to NT & R0 resection remains to be defined. However data from Mayo Clinic suggests that patients with elevated CA 19-9 levels that normalize following NT or patients with CA 19-9 levels remaining within normal range through the course of therapy have improved outcomes.  

The same study suggests that on CT scan 'radiologic anatomic downstaging is uncommon'. Thus all patients with stable disease (no local progression of tumor or development of distant metastases) are advised to undergo surgical exploration.

FDG PET – CT scan can also been utilized to assess response to NT

6.      When is the surgery performed after completion of NT?

Surgery is performed 4-8 weeks following completion of chemoradiotherapy

7.      What are the likely outcomes

The current available data suggests that up to 80% of BRPC & LAPC patients who do not have progressive disease on CT scan and are surgically explored with curative intent will have R0 resection. These patients have also showed decreased lymph node positivity & perineural invasion and as well as improved overall survival.

In one recent study from Johns Hopkins hospital involving 186 patients with BRPC & LAPC patients who underwent NT and subsequent pancreatectomy, 19 (10%) patients had complete pathological response (i.e. no tumor was detected on final histopathology of the surgically removed specimen). The median disease free survival was 26 months and median overall survival in this group of patients is reported to be > 60 months.

Thus the objectives (section 3) with which NT was initiated are being achieved.

To summarize, NT has emerged as a promising option that offers possibility of curative surgery (R0) for patients with BRPC / LAPC, many of whom can even have long term survival.  

References

1. Kaufmann B, Hartmann D, D'Haese JG et al. Neoadjuvant treatment for borderline resectable pancreatic ductal adenocarcinoma. Dig Surg. 2018. DOI:10.1159/000493466
https://www.karger.com/Article/FullText/493466

2. Jin H, Blair AB, Groot VP et al. Is a pathological complete response following neoadjuvant chemoradiation associated with prolonged survival in patients with pancreatic cancer? Ann Surg. 2018;268(1):1-8
https://journals.lww.com/annalsofsurgery/fulltext/2018/07000/Is_a_Pathological_Complete_Response_Following.1.aspx

3. Michelakos T, Pergolini I, Castillo CF et al. Predictors of resectability and survival in patients with borderline and locally advanced pancreatic cancer who underwent neoadjuvant treatment with FOLFIRINOX. Ann Surg. 2019;269(4):733-740
https://journals.lww.com/annalsofsurgery/fulltext/2019/04000/Predictors_of_Resectability_and_Survival_in.21.aspx

4. Truty MJ, Kendrick ML, Nagorney DM et al. Factors predicting response, preoperative outcomes and survival following total neoadjuvant therapy for borderline / locally advanced pancreatic cancer. Ann Surg. 2019. DOI:10.1097/SLA.0000000000003284

https://journals.lww.com/annalsofsurgery/Abstract/publishahead/Factors_Predicting_Response,_Perioperative.95162.aspx

5. Murphy JE, Wo JY, Ryan DP et al. Total neoadjuvant therapywith FOLFIRINOX in combination 

with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: A phase 2 

trial. JAMA Oncol. 2019. DOI: 10.1001/jamaoncol.2019.0892

https://www.ncbi.nlm.nih.gov/pubmed/31145418

Authors:

Dr Nitin Vashistha, MS, FIAGES, FACS

Dr Dinesh Singhal, MS, FACS, DNB (Surg Gastro)

Department of Surgical Gastroenterology,
Max Super Speciality Hospital, Saket, New Delhi, India
E mail: gi.cancer.india@gmail.com


Suggested reading:
https://www.pancan.org/facing-pancreatic-cancer/treatment/treatment-types/chemotherapy/
https://www.pancan.org/facing-pancreatic-cancer/treatment/treatment-types/radiation-therapy/