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.

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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/

Changing paradigms in Surgery of the Pancreas: What it means for the patients

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'noli me tangere' -  Latin phrase for 'Touch Me Not'

According to the Wikipedia, the organ that typically fits the description of this phrase is the pancreas. This is due to some of the perceived attributes of pancreas and its surgery - the location of pancreas with resultant difficulty in accessing it during 'routine' abdominal operations, its close relation to major blood vessels and significant morbidity of pancreatic operations.

No wonder the maxim "eat when you can, sleep when you can, don't mess with the pancreas" was a common surgical anecdote. In the current times, such wisecracks are merely of historical interest and no longer hold any validity.

Emergence of specialized pancreatic surgeons with better understanding of pancreatic diseases & refined surgical techniques coupled with an effective management of procedure related complications has resulted in the current era of pancreatic surgery with low mortality and acceptable morbidity.

Modern pancreatic surgery can aptly be described as being safe, elegant, patient friendly surgery that is based on highest quality medical research ('medical evidence') and increasing utilizes minimally invasive surgery techniques such as robotic surgery.

Over last 2 decades, notable advancements have been made in all domains of pancreatic surgery for:

1.      Pancreratic necrosis following severe acute pancreatitis

2.      Chronic pancreatitis

3.      Pancreatic cancer

These are briefly discussed in following sections.

1.      Surgery for infected pancreratic necrosis following severe acute pancreatitis (SAP)

SAP with bacterial infection of pancreatic necrosis is one of most serious pancreatic diseases that necessitates intervention for salvage. About a decade ago, this disease entity was treated by open surgical removal of dead peripancreratic tissue ('necrosectomy') – a procedure associated with high mortality and complication rates.

Over the last decade, 'Step Up Approach' has emerged as the preferred alternative treatment strategy for SAP patients with infected necrosis. As an initial management, surgical drains are placed in such infected collections under CT scan guidance. This minimally invasive approach may help avoid further surgical intervention in up to 2/3 of SAP patients with infected necrosis. The patients who do not adequately respond to such drain placement are advised to undergo a laparoscopic necrosectomy.Modern management of infected pancreatic necrosis has thus evolved towards more patient friendly minimally invasive interventions with better outcomes.

2.      Surgery for chronic pancreatitis (CP)

The aim of treatment for patients with CP is lasting relief of pain and available options include endoscopic therapy and surgery. It is pertinent to add that pancreatic ductal stones in the absence of pain do not require any further treatment. High impact studies over last 10 years show that following endotherapy, pain is likely to recur in up to 2/3 of patients within 2 years. In contrast, surgery for CP has several advantages. It can be performed safely with minimal blood loss and postoperative complications and offers a lasting pain relief in up to 80% patients. Also there is emerging evidence that an early surgery may lead to preservation of pancreatic function.

Minimally invasive surgical techniques are being increasing utilized which make surgery for CP more acceptable option than ever before.

3.      Whipple's procedure for resectable cancer of head of the pancreas

 Whipple's procedure is the only currently available treatment that can potentially provide long term survival for pancreatic head cancer. Emergence of specialized pancreatic surgeons, refinements in surgical techniques and image guided, effective management of complications have resulted in mortality of Whipple's procedure ranging between 1-5% at centers of excellence

With safety of the Whipple's procedure no longer a matter of debate, novel strategies are now being adapted to expand the indications of surgery. These include the concept of 'Borderline Resectable Pancreas Cancer' and initiation of neoadjuvant therapy to downstage the disease in order to make it amenable for margin negative resection.

Also in line with other domains of pancreatic surgery, minimally invasive surgery techniques such as robotic assisted surgery are being increasing utilized for Whipple's procedure without any compromise on quality or safety of surgery.

Dr Nitin Vashistha

Dr Dinesh Singhal

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

Understanding Pancreatic Tumors: What Manohar Parrikar & Steve Jobs fought with dignity

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Several prominent members of the civil society - much loved and respected political leaders, film stars and IT industry pioneers in India and abroad have lately been diagnosed with pancreatic tumors leading to much public interest and headlines on the social media. The dignity and determination with which each one of them faced the disease shall be an inspiration for one and all.

The generic term ‘pancreatic tumors’ includes pancreatic cancers (medically known as pancreatic ductal adenocarcinoma or PDAC), neuroendocrine tumors (NET) and cystic tumors. These tumors differ in terms of investigations and treatment strategies (no surgical intervention i.e. observation for some cystic tumors to major pancreatic resections for cancers and NET). They also differ in biological behaviour and outcomes (NET and cystic tumors often are slow growing and have an indolent behaviour as compared to pancreatic cancer).

For all pancreatic tumors, pancreatic protocol abdominal CT scan with is an essential part of diagnostic work up and may reveal one of the clinical scenarios:

1.      Localized disease (confined to the pancreas and surrounding (regional) lymph nodes):

For patients who are medically fit to undertake major surgery, upfront pancreatic resection (i.e. surgical removal) is the best treatment option that provides chances of long-term survival or cure.

Surgery involves removal of a part of pancreas (depending of tumor location) along with lymph nodes that drain this section of pancreas. Thus, tumors located in the body and tail of pancreas are removed by distal pancreatectomy whereas tumors in the head, neck or uncinate process require a more complex operation - Whipple’s procedure or pancreatoduodenectomy.

There have been several advancements in imaging, surgical techniques and critical care that have made pancreatic surgery more patient friendly and safer (reported mortality of 1-5% for Whipple’s procedure from centres of excellence). Some of the notable recent advances include:

- Increased utilization of laparoscopic / robotic techniques so as to avoid large incisions

- Interventional radiology techniques for management of complications

2.      Locally advanced pancreatic cancer (limited involvement of adjacent major vessels, borderline resectable):

Novel chemo & radiotherapy protocols have been introduced in clinical practice with an intent to downstage such tumors and make them resectable. According to current medical literature, up to 20% of such tumors can now be successfully down staged to undergo curative surgery

3.      Advanced tumors (spread to other organs such as liver, lungs or peritoneum i.e. metastatic) or where curative surgery is not feasible due to serious medical conditions:

In such patients, the aim is to provide good quality of life with multidisciplinary management involving endoscopy, chemotherapy and pain management services. In many patients extended survival is possible.

In summary, for medically fit patients with pancreatic cancer confined to the pancreas, surgery is the best treatment option where long-term survival or cure is feasible. For borderline resectable tumors, successful management protocols for down staging such tumors are available. For patients with metastatic disease, emphasis is on providing good quality of life that may also help extend survival.

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