Inorganica Chimica Acta 496 (2019) 119037

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Review article

Platinum compounds: Their continued impact on ovarian cancer treatment T

⁎
Franco M. Muggia , Maria Garcia Jimenez, Pooja Murthy
Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA

A R T I C LE I N FO A B S T R A C T

Keywords: Ovarian cancer treatment became ‘platinum-based’ with the approval of cisplatin by the United States Food &
Cisplatin Drug Administration (FDA) in 1979 based on work sponsored by the National Cancer Institute (NCI). The drug
Carboplatin proved to be dramatically effective in spite of its usually advanced stage at diagnosis. Emesis and nephro-, neuro-
Ovarian cancer and oto-toxicities were major challenges frequently faced by patients during treatment. Carboplatin retained the
DNA repair and BRCA genes
efficacy of cisplatin against ovarian and other related cancers and displaced cisplatin as part of standard
Homologous recombination
treatment during the last three decades. Refinements in treatment of these cancers have more recently come
Poly-(ADP) ribose polymerase (PARP)
inhibitors from understanding the role of DNA repair deficiencies as the cause of vulnerability to these platinum drugs, and
the integration of drugs inhibiting cellular repair mechanisms, and finally by targeting the tumor micro-en-
vironment to recruit new blood vessels and cellular immunity.

1. Introduction spread. Efforts to provide favorable conditions for chemotherapy by

Cisplatin received approval by the Food & Drug Administration
(FDA) for the treatment of ovarian cancer 40 years ago following its
eight years in clinical development by the National Cancer Institute
(NCI) clinical trials program under sponsorship by the Cancer Therapy
Evaluation Program (CTEP) [1]. Its unprecedented activity in helping to
achieve consistent and longer responses in this disease, coupled with
very high rate of cures in advanced germ cell tumors of testicular and
other origins stimulated its clinical development and the subsequent
search for less toxic analogs for the treatment of these and other can-
cers. This review focuses on the early clinical trials principally under
NCI sponsorship and how cisplatin and other platinum compounds re-
volutionized the treatment of ovarian and related gynecologic cancers.
Recent insights into DNA repair pathways and on immunologic effects
with implications of the microenvironment on cancer cell vulnerability
represent future areas of study also involving platinums. Such research
promises to continue expanding our knowledge on the action of these
powerful drugs, more than 50 years cisplatin’s discovery [2].
2. Discussion
2.1. Ovarian cancer treatment in the pre-platinum era
Up to the early 1970s gynecologic oncology efforts focused on the
role of debulking surgery to best address the common scenario of the
common presentations at advanced stages that relate to early peritoneal
extensive surgeries occasionally yielded striking long lasting benefit
after laborious cytoreductions leading to ‘optimal’ residual nodules
after such surgery (initially defined as less than 2 cm in diameter and
more recently requiring either less than one centimeter or no gross
residuum) complemented by alkylating agents. Second-look reassess-
ment were routinely done in some centers such as MD Anderson, and a
few percent of patients were identified who had no evidence of residual
disease after melphalan or cyclophosphamide. The status of ovarian
cancer trials based on surgery, radiation, and alkylating agents prior to
cisplatin were the subject of discussion at the US-USSR exchange at the
Petrov Institute in Leningrad in 1976 and later succinctly summarized
in reviews prior to the impact of cisplatin [3]. Soon thereafter, how-
ever, studies initiated in London and New York, and subsequently in
Amsterdam and in Rochester, Minnesota were to produce striking ef-
fects that heralded the use of cisplatin in ovarian cancer [4,5]. How-
ever, in spite of consistent demonstrations of a survival advantage when
cisplatin was compared to combination chemotherapy without cis-
platin, the occurrence of severe vomiting and some unpredictable major
toxicities required addressing for cisplatin to be consistently adopted in
first line treatments. Protection against emesis was a key step in im-
proving quality of life during platinum based chemotherapy and
achieving optimal dose-intensity of platinum administration. Another
major step was the development of a less emetogenic and generally less
nephro-, oto-, and neuro-toxic analog, carboplatin (covered by Calvert
in this supplement) [6,7].

⁎
Corresponding author.
E-mail address: franco.muggia@nyulangone.org (F.M. Muggia).

https://doi.org/10.1016/j.ica.2019.119037
Received 17 May 2019; Received in revised form 21 July 2019; Accepted 22 July 2019
Available online 23 July 2019
0020-1693/ © 2019 Elsevier B.V. All rights reserved.
F.M. Muggia, et al.
2.2. Impact of cisplatin and later analogues on ovarian cancer treatment
As in testicular cancer, the impact of cisplatin on the survival of
women with ovarian cancer was soon obvious compared to alkylating
agent or to newly forged combinations under sponsorship of the NCI’s
Chemotherapy Program and of related research endeavors in UK,
Europe, and Japan burgeoning the 1970s. Most notable was a Mayo
Clinic randomized study of cisplatin versus cyclophosphamide [8] that
was stopped after an entry of 34 patients with ovarian cancer because of
median progression-free survival favoring cisplatin exceeding one year.
Combination chemotherapy still prevailed among studies into the
1980s with results uniformly favoring cisplatin-containing regimens
with suggestions of improved results with higher platinum dose-in-
tensity [9]. More than a decade later, cisplatin by itself yielded similar
results in ovarian cancer when compared to the newly established re-
ference combination of paclitaxel + Cisplatin by Gynecologic Oncology
Group study GOG132 [10]. By then, carboplatin had also undergone
phase I and II clinical development and a study by UK and Europe in-
vestigators randomized their choice of single agent Carboplatin or a
50 mg/m2/cycle Cisplatin combination with doxorubicin and cyclo-
phosphamide (CAP) versus their new standard paclitaxel + carboplatin
(ICON2) [11] Both of these studies demonstrated that untreated
ovarian cancer was uniquely susceptible to single-agent platinums and
that the addition of other drugs, including paclitaxel did not greatly
impact initial benefits in chemotherapy naïve ovarian cancers. The
large Bristol Myers Squibb data base of Carboplatin ovarian cancer
outcomes in relation to dose calculated by Area Under the Curve (AUC)
developed by Calvert is consistent with the finding that Carboplatin
responsiveness is greater when ovarian cancer is first diagnosed than
later when patients receive the drug for ‘platinum sensitive’ recurrence
[12]. These findings reinforce the notion that untreated ovarian cancer
is uniquely sensitive to platinum drugs and some degree of platinum
resistance is detectable upon re-exposures.
2.3. Overcoming toxicities of platinum compounds
Emesis was a frequent impediment for completing treatment with
Cisplatin even in uniformly curative situations such as young men
presenting with advanced stage testicular cancer. Some patients failed
to return for curative treatments after prolonged bouts of vomiting.
Moving to NYU Cancer Center and renewing my direct involvement in
patient care (after four years at CTEP, NCI), I recall the challenge in
controlling the excessive vomiting faced by our ovarian cancer patients
on our cisplatin 20 mg/m2/day × 5 + cyclophosphamide and the in-
adequate antiemetic program ABCD (Ativan for lorezapam, Benadryl,
Compazine and dexamethasone) preceding Cisplatin. Our regimen was
largely accomplished because of a special in-patient facility dubbed
Cooperative Care where patients and their care partners shared in-pa-
tient rooms where they could rest after receiving the drug, and able to
return for additional hydration or premedication at nursing stations.
While the results of this treatment protocol [13] appeared superior
compared to others utilizing attenuated doses of Cisplatin [5] we did
encounter some severe toxicities (e.g. recall a serum sodium of
108 mEq/dL) due to excessive use of hydration, mannitol, and in-
tractable vomiting. These issues have been largely forgotten upon the
development of HT3 anti-emetics specifically introduced to enable pa-
tients to be able to receive cisplatin without fear of several days of
nausea and vomiting. In fact, Carboplatin was selected to replace cis-
platin because of its low emetogenic potential coupled with lesser
toxicities to kidneys, sensory nerves, and hearing [2].
2.4. Optimizing drug dosing and intraperitoneal delivery
Since the 1970s, a search for analogs of Cisplatin with better ther-
apeutic index and exploration of platinum chemistry for greater anti-
tumor selectivity has taken place. The clinical development of
2
Inorganica Chimica Acta 496 (2019) 119037
Carboplatin as a 2nd – generation platinum by Bristol Myers Squibb was
the one that convincingly succeeded in largely replacing the parent
compound, particularly in ovarian cancer [14]. Among its attributes
was lesser propensity to induce vomiting in the ferret model developed
by Ken Harrap; this better tolerance relative to other non-nephrotoxic
analogs was subsequently vastly confirmed in a large phase II study in
women with uterine cancer of the cervix [15]. Dosing based on phar-
macodynamic effects on platelets or on AUC-guided findings, were in-
dependently respectively introduced by Merrill Egorin [16] and Hilary
Calvert [17], with the Calvert formula based on renal + non-renal
clearance component eventually becoming universally adopted with a
strong record of safety with exceptions among extremes in body weight
mostly resulting from limitations of calculated creatinine clearances in
lieu of direct assessment of glomerular filtration rate utilized in Cal-
vert’s original study [17]. Carboplatin largely replaced Cisplatin in the
treatment of ovarian cancer after the non-inferiority trial conducted by
Ozols for the Gynecologic Oncology Group (GOG) [14]. With this re-
newed focus, an effort for greater precision in Carboplatin dosing in-
stead of relying on glomerular filtration rates calculated from serum
creatinine is being revisited by ancillary studies instituted by this group
in 2019 (Principal Investigator: Jan Beumer].
Dose-intensifying cisplatin by the intravenous (IV) route appeared
to reach a plateau in terms of benefits in prospective and retrospective
databases [12]. However, a number of studies by the GOG demon-
strated improved hazard ratios favoring intraperitoneal (IP) over IV
administration for progression-free survival and in two such trials also
for overall survival [18]. The last and largest GOG study #262 that also
included an arm with IP carboplatin and shared administration of
weekly paclitaxel and IV bevacizumab has not shown an advantage of
either the IP Carboplatin arm or the IP Cisplatin and IP paclitaxel arm in
this first comparative study with the IV Carboplatin and paclitaxel
control in progression-free survival [19]. It remains to be seen whether
subsets of patients with high-grade serous cancer and BRCA mutations
benefit from the dose-intensification of IP drug delivery against the
predominant peritoneal spread of fallopian tube primaries. While this
last GOG study practically reverses the National Cancer Institute 2005
Announcement emphasizing the survival advantages of GOG172 [20], a
Dutch study utilizing IP Cisplatin, sodium thiosulfate kidney protection,
and hyperthermia (HIPEC) after 3 cycles of neoadjuvant chemotherapy
showed a survival advantage for IP over IV administration [21]. An-
other large study from Japan comparing IP versus IV administration of
Carboplatin, both with IV paclitaxel completed accrual in 2018 and
results are awaited [22]. Carboplatin tolerance by the IP route may
prove advantageous in determining the role of IP therapy for selected
subset of patients with stage III ovarian cancer.
2.5. Ovarian cancer treatment in the genomic era (‘precision medicine’)
Treatment of most malignancies has been ‘personalized’ with the
advent of genomic platforms that underscored the heterogeneity in-
herent in a wide variety of cancers. In ovarian cancers of epithelial
origin (distinguished from the rare stromal and germ cell cancers that
usually arise shortly post-adolescence), pathologists had classified low
and high-grade subtypes, and among the latter the majority were pa-
pillary serous, followed by endometrioid and clear cell [23]. In-
cidentally discovered epithelial ovarian cancers in stage I, serous sub-
types are under-represented – likely because high-grade serous cancers
often originate in the Fallopian tubes and not in the ovary, as re-
cognized by risk reducing surgeries done in carriers of hereditary
conditions (see next paragraph and sections below on BRCA genes).
High grade serous cancers are most often detected in stage III as a result
of the ovaries and the adjacent peritoneum becoming affected from the
enveloping neighboring fimbria.
GOG studies, since 2015 continuing under the NRG Oncology um-
brella continue to set the standards of the chemotherapy backbone for
‘ovarian’ cancer treatment. Phase III studies randomizing the vascular
F.M. Muggia, et al. Inorganica Chimica Acta 496 (2019) 119037

Table 1
Phase III trials with immune check-point inhibitors in ovarian cancer.
NCT number Checkpoint Other drugs Study design Eligibility End points
inhibitor

NCT02580058 Avelumab PLD Phase III - Platinum resistant, refractory Primary:

Arm 1: ovarian cancer OS
Avelumab PFS
Arm 2: Secondary:
Avelumab + PLD OR
Arm 3: PFS
PLD DR
DC
NCT03038100
(IMAGyn)
Atezolizumab Paclitaxel
Carboplatin
Phase III
Arm 1:
• -Histologic diagnosis of
epithelial ovarian cancer,
Primary:
PFS
Bevacizumab Atezolizumab + Paclitaxel + Carboplatin + Bevacizumab peritoneal primary carcinoma, OS
Arm 2: or fallopian tube cancer Secondary:
Placebo + Paclitaxel + Carboplatin + Bevacizumab OR
DR
AE
NCT02891824 Atezolizumab Avastin Phase III - histologically confirmed Primary:
(ATALANTE) Chemotherapy Arm 1: progressive non-mucinous PFS
Placebo + Avastin + platinum-based chemotherapy epithelial ovarian cancer, Secondary:
Arm 2: primary peritoneal, or OS
Atezolizumab + Avastin + platinum-based chemotherapy fallopian-tube adenocarcinoma AE
- Relapsed disease
- 1 or 2 lines of chemo
NCT02718417 Avelumab Carboplatin Phase III - Histological Stage III-IV Primary:
(JAVELIN Paclitaxel Arm 1: epithelial ovarian, fallopian PFS
OVARIAN 100) Chemotherapy, then observation tube, or primary peritoneal Secondary:
Arm 2: cancer OS
Chemotherapy, Avelumab maintenance Maintenance
Arm 3: PFS
Chemotherapy + Avelumab, Avelumab maintenance DR
ORR
NCT02839707 Bevacizumab PLD Phase III - High grade ovarian cancer Primary:
Atezolizumab Arm 1: - Recurrent, platinum resistant Incidence of
PLD + Atezolizumab ovarian cancer DLT
Arm 2: - 1-2 prior regimens OS
PLD + Atezolizumab + Bevacizumab PFS
Arm 3: Secondary:
PLD + Bevacizumab Disease related
symptoms
Frequency/
Severity of AE
ORR

endothelial growth factor (VEGF) antibody, bevacizumab (Avastin)
versus placebo by GOG and by European groups have demonstrated the
potential for ‘targeted’ therapies to contribute further in improving
outcomes combined with or following chemotherapy [24]. More re-
cently, cancers arising in BRCA germ line mutation carriers, as well as
in patients with tumors with somatic BRCA mutations, and even with
high-grade serous histology have benefited by treatment with oral poly
(ADP-ribose) polymerase (PARP) drugs (olaparib, rucaparib, niraparib)
that have received approval by the US Food and Drug Administration
(FDA) as maintenance for ovarian cancer after responding to platinum-
based chemotherapy. Olaparib was first approved in 2017 by demon-
strating objective responses in heavily pretreated ovarian cancer, and
all three drugs plus talazoparib are under study as part of initial
treatment after diagnosis or in earlier recurrence settings with
mounting convincing evidence of lengthening the progression-free in-
terval following platinum-based chemotherapy and thesemay result in
improvements in survival (see ovarian cancer summary updated in
www.cancer.gov [25]. The underlying vulnerability of ovarian cancers
to PARP inhibitors had been attributed to their propensity for homo-
logous recombination defects (HRD) resulting from hereditary or so-
matic alterations in BRCA genes, and related genes involved in homo-
logous recombination DNA repair. Examples of their expanding roles
are described in Sections 2.6 and 2.7.
2.6. Impact of BRCA genes discovery on biology of ovarian cancer
In 1992, while attending with epidemiology leader Malcolm Pike an
overview of Mary-Claire King’s studies on hereditary breast and ovarian
cancers as an invited lecture at the annual meeting of the American
Association for Cancer Research (AACR) we learned about the locali-
zation of the breast and ovarian cancer (BRCA) familial susceptibility
genes and the cloning of BRCA1 by Mark Skolnick’s team in Utah.
Commenting on the session, I recall Pike’s comment: “Well, that
changes everything!”. In fact, as we subsequently identified the func-
tion of these genes and began to perform risk-reducing surgeries, we
learned that the majority of high-grade serous ovarian cancers do not
start in the ovary, but actually in the fimbria of the Fallopian tubes!
[26]. Progress in early diagnosis in the breast by MRI, and refining the
classification of ‘ovarian’ cancer ensued pari-passu with preventive
strategies and therapeutic developments [27].
2.7. Adding PARP inhibitors after platinum-based chemotherapy
Mechanism of resistance to PARP inhibitors, and how the emer-
gence of platinum resistance alters their efficacy need to be delineated
in further delineating how they should be optimally sequenced, and
integrated into treatment regimens. A recently treatment patient, best
illustrates this point. While following her endocrine breast cancer
therapy a BRCA1 mutation carrier in her 40s had elevated epithelial

3
F.M. Muggia, et al.
markers and eventually was diagnosed and staged as IIB with a high-
grade serous ovarian cancer. Four years after a complete pathologic
response with Cisplatin IP and paclitaxel IV she again manifested rise in
CA125 and over a period of 5 months, this appeared to related princi-
pally to a 2 cm nodule just posterior to the bladder that was eventually
removed laparoscopically. Olaparib was thereafter started and she re-
mains in complete marker and radiographic response with minimal side
(occasional nausea) effects one year later. Such treatment in lieu of
reinduction with a platinum illustrates concerning the unknown po-
tential for these drugs to be used earlier in the course of these cancers.
2.8. Integration of ‘targeted therapies’ and immunotherapy
The advent of immune-oncology and their brilliant therapeutic re-
sults in melanoma is slowly expanding in a number of other cancers.
Immune-checkpoint inhibitors’ role in ovarian cancer remain undefined
but were encouraging enough [28] to stimulate a number of phase III
trials for ovarian cancer patients (Table 1). This literature supports
some activity for anti-PD1 or PD-L1 strategies, even in heavily pre-
treated patients and including chemotherapy reintroduction showing a
potential for increasing benefit [29]. Evidence that platinum drugs
differ in their abilities to affect the tumor microenvironment and T cell
and macrophage functions [30] is accumulating and is being tested
clinically with new platinum analogs such as Phosplatin (being studied
in combination with the anti-PD1 drug, Avelumab) [31]. Other factors
that may enhance the sensitivity of ovarian cancer to Carboplatin, such
as after pretreatment with antimalarials are illustrated in a recent case
report [32].
3. Summary
This review emphasizes how cisplatin’s introduction began a dra-
matic evolution in the treatment of ovarian cancer, and continues to
provide key leads for further improvements by evolving from purely
empiric observation to increasing guidance from cancers genomics.
Recent examples point to the continuing central role of platinum drugs
in this era of ‘precision medicine’, especially focusing on how gyneco-
logic cancer vulnerability is related to inability to repair DNA after
exposure to platinums. Treatment of other ‘platinum-sensitive’ cancers
–such as those of pulmonary, gastrointestinal and urological origins–
parallel to some extent this continued evolution in cancer therapeutics
that involve building on the robust chemotherapy backbone provided
by Cisplatin and 2nd generation platinum drugs that are in clinical use.
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