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Table of Contents
EDITORIAL
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 97-100

Robotic surgery, proton therapy, and targeted therapy – Are these the way forward in oncology?


Department of Radiation Oncology, Manipal Hospital, New Delhi, India

Date of Web Publication10-Jan-2020

Correspondence Address:
Dr. Anusheel Munshi
Department of Radiation Oncology, Manipal Hospital, Dwarka, New Delhi - 110 075
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJNO.IJNO_19_19

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How to cite this article:
Munshi A, Rastogi K. Robotic surgery, proton therapy, and targeted therapy – Are these the way forward in oncology?. Int J Neurooncol 2019;2:97-100

How to cite this URL:
Munshi A, Rastogi K. Robotic surgery, proton therapy, and targeted therapy – Are these the way forward in oncology?. Int J Neurooncol [serial online] 2019 [cited 2020 Aug 15];2:97-100. Available from: http://www.Internationaljneurooncology.com/text.asp?2019/2/2/97/275536




  Introduction Top


Cancer is one of the leading causes of global morbidity and mortality. According to the World Health Organization, cancer was the second leading cause of death in 2015 and accounted for 8.8 million deaths. Furthermore, the number of new cancer cases is expected to rise by about 70% over the next two decades. Further, approximately 70% of deaths from cancer occur in low- and middle-income countries. This growing incidence and prevalence of cancer augmented with launch of novel cancer therapy and coupled with increasing awareness about cancer cure and treatment are likely to drive the growth of the global cancer therapy market in the upcoming years.

The management of oncology has conventionally hinged on the three cornerstones of medical, surgical, and radiation oncology. More than 80% patients are likely to need dual or triple modalities. Strides of technological advancements have happened in each of these disciplines, although with disproportionately increasing cost burden. In some cases, the high costs have not been justified by the results. This article takes an example, each from medical, surgical, and radiation oncology to illustrate poor cost-benefit ratio of some emerging oncology treatments.


  Robotic Surgery – surgical Oncology Top


Minimal surgery has been the desire of patients and surgeons alike for ages. The first steps toward minimally invasive surgery began in 1987 with the first laparoscopic cholecystectomy. Its advantages include popularity among surgeons, patients, and insurance companies. 30 years ago, a landmark in the surgical field was achieved when a robot was first used in a surgical theater. In 1985, the robot PUMA 200 (Westinghouse Electric, Pittsburgh, PA) did a computed tomography (CT)-guided brain biopsy.[1] In the 1990s, “master-slave” robot, were developed, which had a robot with remote manipulators and these were controlled by a surgeon at a surgical workstation.[1]

The da Vinci robot was soon approved by international agencies and surgeons from across continents have proved its use and safety for varied robot-assisted surgeries.

Some of the euphoria with robotics is related to the surgical benefits it offers over traditional surgical methods. Stability, integration with modern imaging tools, accuracy, and extreme range of maneuverability are examples of some of these.[2]

It is questionable if “surgical robotics” withstands the litmus test of evidence-based oncology. Comparative studies of robotic and laparoscopic surgical procedures in general surgery have shown similar outcomes for nearly all domains, including perioperative and postoperative complications, oncological outcomes, quality of life, and functional outcomes. In a recent randomized study, 151 patients were treated with open radical retropubic prostatectomy and 157 underwent robot-assisted laparoscopic prostatectomy. There was no difference in urinary function scores at 6 months, 12 months, or 24 months after surgery. Similarly, there was no difference in sexual function scores or biochemical recurrences.[3] It is interesting that there was no difference in robotic prostatectomy even when compared with the traditional open surgery (the likelihood of any difference as compared to laparoscopic surgery is perhaps even lesser).

To compound problems, a recent randomized study among men with localized prostate cancer, with a decent 12.7 years median follow-up did not find that surgery was associated with significantly lower all-cause or prostate-cancer mortality than observation.[4] The patients in this study were medically fit for radical prostatectomy and had histologically confirmed, clinically localized prostate cancer stage T1-T2NxM0. This is typically the group of patients that is taken up for “robotic surgery” or “proton therapy.” As the study shows, these patients need neither.

The phenomenon is not confined to prostate cancer. The recently reported results of the laparoscopic approach to cervical cancer (LACC) Trial, a phase 3 trial comparing minimally invasive (laparoscopic or robotic) radical hysterectomy with open radical hysterectomy in women with early-stage cervical cancer are revealing. Midway through the trial, the data and safety monitoring committee had to give a call for early closure of the trial. The interim analysis revealed a lower 3-year rate of overall survival (93.8% vs. 99.0%; hazard ratio for death, 6.00).[5] A companion population-based study by Melamed et al. showed similar results.[6] More worrisome was a recent publication related to bladder cancer where robotic cystectomy was associated with higher rates of peritoneal carcinomatosis (21% [9 out of 43] vs. 8% [2 out of 26]). Even the extrapelvic recurrences were higher when compared with open radical cystectomy.[7]

The prime problem area with robotic technology is the higher cost of equipment, which in turn translates to greater financial toxicity for patients. Problems of lesser importance could include the lack of haptic feedback. To be successful, the recipe for robotic surgery is simple: The first aim should be to reduce the costs and evolve new cost-effective platforms and technologies. Subsequent attention may be given to standardize the platforms and simulators and to generate high-quality evidence to support use of this technology.


  Proton Therapy – radiation Oncology Top


Technologies titles such as Gamma knife, Cyberknife, Tomodirect, and Trubeam do sound impressive. The latest addition to this list is Proton therapy. Proton therapy actually made a relatively humble beginning with only 2 units existing in US in 2004. However, proton therapy thereafter has taken a flight of its own from there, taking off from a totally new aerodrome, in a pristine fighter jet. At present, according to the Particle Therapy Co-Operative Group data, 57 proton accelerators used for the treatment of diseases operate in the world. Most of them work in the USA (19), Japan (12), and Germany (6). Another 37 centers with a period of commissioning in 2017–2021 are under construction. According to the sixth edition of the World Proton Therapy report from MEDraysintell, the proton therapy world market is anticipated to reach $1 billion in 2019.[8]

As evident, proton therapy has been riding high on the prostate screening drive and the steady stream of screen detected patients. However, Proton therapy can paradoxically be one of the worst indications for the management of early prostate cancer. Multiple alternatives exist for the treatment of early screen detected prostate cancer, including no treatment at all. At present, there is a good likely hood of insurance refusing the proton therapy reimbursements, and this means that those centers, funded by loans, built on the lines of prostate cancer treatment model will shut shop.[9] Examples are emerging fast. In December 2014, The Indiana University Proton Therapy Center closed down its operations, making it the first proton-beam therapy center in the United States to shut down. University executives and an independent review committee attributed the shutdown to the center's untenable financial losses. Just 3 years after opening its doors, San Diego's only proton therapy center sought bankruptcy protection in 2017.

Firefighting measures have already set in the United States, and other countries are likely to follow suit. The current version of proton therapy needs to deal with several teething issues, including mammoth financial investments, logistics in infrastructure set up, high maintenance cost, severe maintenance issues, costly replacements, inflated patient treatment bills, and insurance issues for patients. New practice models where one machine is shared with several centers, accepting reimbursement of photon therapy for proton treatments are examples of such desperate measures.[10] Other efforts including drastically reducing the size of the area required for set up of these giant machines, including reducing the size of these jumbo machines themselves.

Present-day proton users claim “significant advancements” in their machines as compared to those of yore. These claims include incorporation of on-board cone-beam CT, use of spot scanning rather than scattering, and so on. Such advancements, one could counter argue have increased the cost of the machines (and consequently the financial toxicity) even higher, without commensurate proven benefits.

Unless drastic measures are taken by vendors and related agencies in time, the 250 million dollar “white elephants” are likely to be a thing of the past very soon. If proton therapy has to survive, it has to get its size, its price and treatment cost for the patient, within the confidence interval of the cost of photon therapy![11],[12] Even then, it might struggle in the face of near negligible robust evidence to support proton therapy.


  Targeted Therapy – medical Oncology Top


Global cancer drugs market is expected to fetch $111,938.4 million by 2020, registering a compound annual growth rate of 7.1% during the forecast period 2014–2020.[13] The drugs prescribed in targeted therapy treatment often range from monthly averages of $5000 to $10,000. Orphan drugs, which are used to treat “rare” diseases, can cost $300,000 or more per year.

Targeted therapies are agents that are meant to block the growth and spread of cancer by interfering with specific molecular targets related to cancer that are involved in the growth, progression, and spread of cancer.[14] These therapies got a headstart with Imatinib, a molecular-targeted drug used for the treatment of chronic myeloid leukemia (CML). This selective BCR-Abl tyrosine kinase inhibitor suppresses the growth of Philadelphia chromosome-positive CML, selectively sparing normal. After a median follow-up of 19 months, the estimated rate of a major cytogenetic response (0%–35% of cells in metaphase positive for the Philadelphia chromosome) at 18 months was 87.1% (95% confidence interval, 84.1–90.0) in the Imatinib group and 34.7% (95% confidence interval, 29.3–40.0) in the group given interferon alfa plus cytarabine (P < 0.001) cells.[15] Indeed, this drug dramatically changed the course and outcome of CML. Subsequent success stories were far and few and included agents such as herceptin for breast cancer. Overall subsequent “targeted therapies” have been pale in comparison while escalating ever high in cost. There are other problems as well. A study assessed 47 new molecular entities approved by the Food and Drug Administration (FDA) between 2011 and 2015. These 47 drugs were authorized for 69 FDA approved indications, whereas the NCCN recommended these drugs for 113 indications.[16] Off-label use accounts for sizable annual expenditures in the United States, and some estimate it is as much as half of all oncologic care.[17] Interestingly, 86% of NCCN guidelines members have been reported to have financial ties to the industry, 84% receive personal payments and 47% receive research payments. This severe conflict of interest leads to more optimistic conclusions in gray zone clinical indications.[18],[19],[20],[21]

A consistent “lowering the bar” phenomenon is also noticeable with regard to targeted therapy. Replacing the hard endpoint of “overall survival” with softer milestones such as “disease-free survival,” “distant metastasis-free survival,” “stable disease,” and “clinical benefit rate” are examples of these. It is also well known that phase II trials generally give a much higher measure of drug activity and response rate as compared with phase III studies.[19] A prominent example is the use of high dose chemotherapy and salvage autologous stem cell transplant for women with breast cancer. This gained prominence by uncontrolled, phase II studies and was duly contradicted by at least six randomized controlled trials.[22]

The other hurdle in most targeted therapy agents is to determine if maintenance treatment provides improved survival outcomes once the cancer is in remission. Currently, many guidelines state “continuing till progression” which causes added financial drain to strained pockets of cancer patients.

To summarize, present-day management of cancer includes radiotherapy, surgery, systemic therapy and a wide range of supportive and diagnostic services. Riding on the wave of popularity and jingoism, many treatment modalities, not supported by evidence, emerge from time to time. The need of the hour is to encourage evidence-based practice and weed out wasteful techniques and procedures, as these are a constant drain on economy, both of the developed as well as the developing world.



 
  References Top

1.
Kwoh YS, Hou J, Jonckheere EA, Hayati S. A robot with improved absolute positioning accuracy for CT guided stereotactic brain surgery. IEEE Trans Biomed Eng 1988;35:153-60.  Back to cited text no. 1
    
2.
Pugin F, Bucher P, Morel P. History of robotic surgery: From AESOP® and ZEUS® to da vinci®. J Visc Surg 2011;148:e3-8.  Back to cited text no. 2
    
3.
Coughlin GD, Yaxley JW, Chambers SK, Occhipinti S, Samaratunga H, Zajdlewicz L, et al. Robot-assisted laparoscopic prostatectomy versus open radical retropubic prostatectomy: 24-month outcomes from a randomised controlled study. Lancet Oncol 2018;19:1051-60.  Back to cited text no. 3
    
4.
Wilt TJ, Jones KM, Barry MJ, Andriole GL, Culkin D, Wheeler T, et al. Follow-up of prostatectomy versus observation for early prostate cancer. N Engl J Med 2017;377:132-42.  Back to cited text no. 4
    
5.
Ramirez PT, Frumovitz M, Pareja R, Lopez A, Vieira M, Ribeiro R, et al. Minimally invasive versus abdominal radical hysterectomy for cervical cancer. N Engl J Med 2018;379:1895-904.  Back to cited text no. 5
    
6.
Melamed A, Margul DJ, Chen L, Keating NL, Del Carmen MG, Yang J, et al. Survival after minimally invasive radical hysterectomy for early-stage cervical cancer. N Engl J Med 2018;379:1905-14.  Back to cited text no. 6
    
7.
Nguyen DP, Al Hussein Al Awamlh B, Wu X, O'Malley P, Inoyatov IM, Ayangbesan A, et al. Recurrence patterns after open and robot-assisted radical cystectomy for bladder cancer. Eur Urol 2015;68:399-405.  Back to cited text no. 7
    
8.
Proton Therapy World Market Report & Director. 6th ed; 2019. Available from: http://www.medraysintell.com/resources/Proton%20Therapy%20Market%20Report%20and%20Directory%202018%20-%20Presentation.pdf. [Last accessed on 2018 Oct 01].  Back to cited text no. 8
    
9.
Johnstone PA, Kerstiens J. Reconciling reimbursement for proton therapy. Int J Radiat Oncol Biol Phys 2016;95:9-10.  Back to cited text no. 9
    
10.
Bekelman JE, Hahn SM. Reference pricing with evidence development: A way forward for proton therapy. J Clin Oncol 2014;32:1540-2.  Back to cited text no. 10
    
11.
Klein EE, Bradley J. Single-room proton radiation therapy systems: No small change. Int J Radiat Oncol Biol Phys 2016;95:147-8.  Back to cited text no. 11
    
12.
Schippers JM. Miniaturizing proton therapy: A Technical challenge with unclear clinical impact. Int J Radiat Oncol Biol Phys 2016;95:149-53.  Back to cited text no. 12
    
13.
Oncology/Cancer Drugs Market by Therapeutic Modalities (Chemotherapy, Targeted Therapy, Immunotherapy, Hormonal), Cancer Types (Blood, Breast, Gastrointestinal, Prostate, Skin, Respiratory/Lung Cancer) – Global Opportunity Analysis and Industry Forecast, 2013 – 2020. Available from: https://www.alliedmarketresearch.com/oncology-cancer-drugs-market. [Last accessed on 2018 Oct 01].  Back to cited text no. 13
    
14.
Joo WD, Visintin I, Mor G. Targeted cancer therapy – are the days of systemic chemotherapy numbered? Maturitas 2013;76:308-14.  Back to cited text no. 14
    
15.
O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004.  Back to cited text no. 15
    
16.
Wagner J, Marquart J, Ruby J, Lammers A, Mailankody S, Kaestner V, et al. Frequency and level of evidence used in recommendations by the national comprehensive cancer network guidelines beyond approvals of the US food and drug administration: Retrospective observational study. BMJ 2018;360:k668.  Back to cited text no. 16
    
17.
Demonaco HJ, Ali A, Hippel Ev. The major role of clinicians in the discovery of off-label drug therapies. Pharmacotherapy 2006;26:323-32.  Back to cited text no. 17
    
18.
Mitchell AP, Basch EM, Dusetzina SB. Financial relationships with industry among national comprehensive cancer network guideline authors. JAMA Oncol 2016;2:1628-31.  Back to cited text no. 18
    
19.
Fugh-Berman A, McDonald CP, Bell AM, Bethards EC, Scialli AR. Promotional tone in reviews of menopausal hormone therapy after the women's health initiative: An analysis of published articles. PLoS Med 2011;8:e1000425.  Back to cited text no. 19
    
20.
De Jesus-Morales K, Prasad V. Closed financial loops: When they happen in government, they're called corruption; in medicine, they're just a footnote. Hastings Cent Rep 2017;47:9-14.  Back to cited text no. 20
    
21.
Zia MI, Siu LL, Pond GR, Chen EX. ComParison of outcomes of phase II studies and subsequent randomized control studies using identical chemotherapeutic regimens. J Clin Oncol 2005;23:6982-91.  Back to cited text no. 21
    
22.
Berry DA, Ueno NT, Johnson MM, Lei X, Caputo J, Rodenhuis S, et al. High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: Overview of 15 randomized trials. J Clin Oncol 2011;29:3214-23.  Back to cited text no. 22
    




 

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