The pulmonary artery hypertension and cancer: PULAHYCA PILOT study. Initial prostanoid therapy in cancer patients with pulmonary hypertension: results from an observational study

Abstract

Background

Cancer is a leading cause of death worldwide, though new therapies have increased patient survival. These therapies, however, have also raised concerns for cardiovascular toxicities, such as cardiomyopathies, coronary artery disease, hypertension and arrhythmias. Pulmonary arterial hypertension (PAH) is a rare condition that carries a poor prognosis and is often diagnosed at an advanced stage. The annual incidence in the general population is estimated to be between 1 and 2 cases per million.

The highest prevalence occurs during the third and fourth decades of life; however, there are cases whose are identified after the sixth decade. It has increasingly become evident that various cancer therapies can exacerbate pulmonary hypertension, significantly impacting patient prognosis. It is recognized that oncologic treatments can cause endothelial dysfunction, including the pulmonary vasculature, and can have thrombotic effects, worsening PAH in patients with this disease.

The objective of this study is to describe our experience with patients with a concomitant diagnosis of PAH and cancer, who received prostanoid therapy to be able to complete specific cancer treatments.

Methods

The PULmonary Artery HYpertension and Cancer (PULAHYCA) pilot study is an observational study of patients with a cancer diagnosis planning to initiate a specific oncologic treatment, with PAH detected during baseline assessment.

Patients with PAH due to group 1and group 4 were included, defined as per the 2022 European Society of Cardiology (ESC) guidelines, that require a mean pulmonary artery pressure (mPAP) greater than 20 mm Hg at rest, increased pulmonary artery resistance of more than 2 Wood units and wedge pressure less than 15 mm Hg.

The PAH risk category was established according to the ESC guidelines and the REVEAL Lite 2 score. Patients with an intermediate risk with a diagnosis of more than 6 months were included.

Results

After screening 349 PH patients, 12 patients were included in the study. All participants had a normal ejection fraction and were treated with a combination of a 5- phosphodiesterase inhibitor, an endothelin receptor antagonist, and treprostinil. Eight patients were classified under group 1 pulmonary hypertension, and four under group 4 pulmonary hypertension. During the 12-month follow-up, patients demonstrated significant clinical and hemodynamic improvement. Functional capacity, measured by the six-minute walk test (6MWT), increased significantly from 325 [304–440] meters at baseline to 401 [315–455] meters at 12 months (p = 0.0014). B-type natriuretic peptide (BNP) levels decreased notably from 321 [205–506] pg/ml to 188 [100–229] pg/ml (p = 0.0001). Pulmonary vascular resistance (PVR) also showed a significant reduction, from 3.8 [3.3–4.2] Woods Units (WU) to 3.5[2.5–3.7] WU (p = 0.00018). All patients survived during the study period and could complete their cancer treatment, which included.

Conclusion

The PULAHYCA PILOT study demonstrates that treatment with subcutaneous Treprostinil in intermediate-risk PH patients undergoing initial oncologic therapy enables completion of cancer treatment, leading to either remission or chronic disease control. Furthermore, beyond the oncologic benefit, patients exhibited improvements in both clinical status and objective markers of pulmonary hypertension severity.

Background

Cancer is a leading cause of death worldwide, though new therapies have increased patient survival [1]. These therapies, however, have also raised concerns for cardiovascular toxicities, such as cardiomyopathies, coronary artery disease, hypertension, and arrhythmias [1, 2].

Pulmonary arterial hypertension (PAH) is a rare condition that carries a poor prognosis and is often diagnosed at an advanced stage. The annual incidence in the general population is estimated to be between 1 and 2 cases per million. The highest prevalence occurs during the third and fourth decades of life; however, there are cases whose are identified after the sixth decade [2, 3].

We know that some cancer therapies cause Pulmonary Hypertension (PH). It has increasingly become evident that various cancer therapies can exacerbate PH, significantly impacting patient prognosis. It is recognized that oncologic treatments can cause endothelial dysfunction, including the pulmonary vasculature, and can have thrombotic effects, worsening PAH in patients with this disease [4–6]. One prime example is dasatinib, a BCR-ABL tyrosine kinase inhibitor (TKI) used in certain types of leukemia. In 2011 the AFSSAPS (L’agence française de sécurité sanitaire des produits de santé) reported on 13 cases of PH that were linked to its use in France. In a randomized trial comparing dasatinib with imatinib, PH was more frequent in the dasatinib group (5.8% versus 2.7%). This risk increased with a longer exposure period [6–9]. The other BCR-ABL TKIs, bosutinib, imatinib, nilotinib and ponatinib, have also been linked to PH, though not as frequently [2, 6, 10–12].

In addition to BCR-ABL TKIs, cases of PH have been attributed to bevacizumab, a vascular endothelial growth factor inhibitor (VEGFi) authorized for the treatment of various types of cancer. Several agents used for the treatment of multiple myeloma add further to the list, including thalidomide, carfilzomib, and bortezomib. Finally, cases of PH have been reported with many alkylating agents, including mitomycin, thiotepa, cyclophosphamide, and ifosfamide.

A sound understanding of the pathophysiological mechanisms involved is lacking and this complicates the management of patients presenting with concomitant PH and requiring cancer therapies, or those who develop it as an adverse event of these therapies. Historically, PH has been a contraindication for cancer treatment due to its high mortality, but advances in specific treatments for PH offer a promising future for patients with these concomitant pathologies.

The objective of this study is to describe our experience with patients with a concomitant diagnosis of PAH and cancer, who received prostanoid therapy to be able to complete specific cancer treatments.

Methods

The PULmonary Artery HYpertension and Cancer (PULAHYCA) pilot study is an observational study of patients with a cancer diagnosis planning to initiate a specific oncologic treatment, with PAH detected during baseline assessment.

Patients with PAH due to group 1and group 4 were included, defined as per the 2022 European Society of Cardiology (ESC) guidelines, that require a mean pulmonary artery pressure (mPAP) greater than 20 mm Hg at rest, increased pulmonary artery resistance of more than 2 Wood units and wedge pressure less than 15 mm Hg [3].

The PAH risk category was established according to the ESC guidelines and the REVEAL Lite 2 score. Patients with an intermediate risk with a diagnosis of more than 6 months were included [3, 13–15]. All patients gave their written consent to participate.

Statistical analysis

No sample size calculations were made since all available patients were included. Categorical variables were expressed as frequencies and percentages. Continuous variables were expressed as medians and interquartile ranges. The Friedman test was used to evaluate differences across the time points. Statistical significance was set as a p-value lower than 0.05. Calculations and figures were done with R version 4.3.3.

Results

After screening 349 PH patients, 12 patients were included in the study. The selection process is detailed in Fig. 1. All participants had a normal ejection fraction and were treated with a combination of a 5-phosphodiesterase inhibitor, an endothelin receptor antagonist, and treprostinil. Eight patients were classified under group 1 pulmonary hypertension, and four under group 4 pulmonary hypertension. Their baseline clinical characteristics and measurements are detailed in Table 1.

Fig. 1.

Patient selection flowchat

Table 1.

Basal population characteristics

Age	Primary cancer	Oncological treatment	PH group	TAPSE (mm)	PAMP (mm Hg)	CI (l/min/m2)	PVR (UWoods)	Wedge pressure (mm Hg)	Hematocrit (%)	BNP (pg/ml)	6MWT (m)
48	Breast	Doxorubicin - Cyclophosphamide - Paclitaxel	1	21	33	4	3,7	11	43	343	465
52	Breast	Doxorubicin - Cyclophosphamide - Paclitaxel - Trastuzumab - Pertuzumab	1	18	41	3,8	3,9	9	36	298	432
67	Breast	Trastuzumab - Pertuzumab - Lapatinib	4	16	32	4,7	5	10	31	210	490
39	Breast	Palbociclib - Ribociclib - Exemestane - Everolimus	1	14	39	5,8	3,6	12	39	189	243
69	Prostate	Docetaxel - Leuprolide - Abiraterone	1	14	62	5,1	2,6	12	39	567	210
56	Breast	Doxorubicin - Cyclophosphamide - Paclitaxel	4	12	66	2,6	3,8	13	29	492	287
42	Chronic myeloid leukemia	Imatinib - Nilotinib	1	23	33	5,2	5	11	36	98	390
41	Chronic myeloid leukemia	Imatinib - Nilotinib - Ponatinib	4	16	68	4,1	5	12	32	456	309
55	Breast	Doxorubicin - Cyclophosphamide - Paclitaxel - Trastuzumab - Pertuzumab	1	21	27	3,9	2,6	12	36	547	520
37	Rectum	5-Fluorouracil - Oxaliplatin	4	19	29	4,2	2,6	10	33	109	340
63	Multiple myeloma	Bortezomib - Cyclophosphamide - Dexamethasone - Lenalidomide - Carfilzomib	1	16	43	4,3	4	10	34	219	310
47	Lymphoma	R-CHOP	1	17	48	3,9	3,5	11	30	565	309

PH pulmonary hypertension, TAPSE Tricuspid annular plane systolic excursion, PAMP pulmonary artery mean pressure, CI cardiac index, PVR pulmonary vascular resistance, BNP B-type natriuretic peptide, 6MWT 6-minute walk test

During the 12-month follow-up, patients demonstrated significant clinical and hemodynamic improvement. Functional capacity, measured by the six-minute walk test (6MWT), increased significantly from 325 [304–440] meters at baseline to 401 [315–455] meters at 12 months (p = 0.0014). B-type natriuretic peptide (BNP) levels decreased notably from 321 [205–506] pg/ml to 188 [100–229] pg/ml (p < 0.0001). Pulmonary vascular resistance (PVR) also showed a significant reduction, from 3.8 [3.3–4.2] Woods Units (WU) to 3.5[2.5–3.7] WU (p = 0.00018). In contrast, no significant changes were observed in pulmonary artery systolic pressure (PASP), which remained stable (baseline: 79 [69–88] mm Hg; 12 months: 77 [69–84] mm Hg; p = 0.4538), or in pulmonary artery mean pressure (PAMP), which remained unchanged (baseline: 40 [33–52] mm Hg; 12 months: 40 [32–51] mm Hg; p = 0.8779). The evolution of these variables at different time points is detailed in Table 2 and illustrated in Fig. 2.

Table 2.

Changes in PASP, PAMP, PVR, BNP and 6MWT over time

Characteristic	Basal, N = 121	3 months, N = 121	6 months, N = 121	12 months, N = 121	p-value2
PASP (mm Hg)	79 (69, 88)	78 (76, 88)	79 (69, 88)	77 (69, 84)	0.4538
PAMP (mm Hg)	40 (33, 52)	40 (34, 51)	40 (33, 52)	40 (32, 51)	0.8779
PVR (UWoods)	3,8 (3,3–4,2)	3,8 (3,3–4,2)	3,7 (2,8–4,2)	3,5 (2,5–3,7)	0.00018
BNP (pg/ml)	321 (205, 506)	321 (205, 506)	209 (179, 321)	188 (100, 229)	< 0.0001
6MWT (m)	325 (304, 440)	325 (304, 440)	385 (330, 402)	401 (315, 455)	0.0014
1Median (IQR) 2 Friedman rank sum test

PASP pulmonary artery systolic pressure, PAMP pulmonary artery mean pressure, PVR pulmonary vascular resistance, BNP B-type natriuretic peptide, 6MWT 6-minute walk test

¹ Median (IQR) ² Friedman rank sum test

Fig. 2.

PAMP, PVR, BNP and 6MWT over time

The Functional Class (FC) was collected throughout the study but did not show significant changes.

All patients survived during the study period and could complete their cancer treatment.

Discussion

Cancer and PH are two pathological entities that can coexist in patients, leading to poor prognosis. This coexistence occurs in different scenarios and is thought to share underlying pathophysiological processes.

Cancer therapies are associated with the development of PH by diverse mechanisms. Tyrosine kinase inhibitors as dasatinib, proteasome inhibitors as carfilzomib, anti-angiogenic agents as bevacizumab, mitomycin C, and alkylating agents, among others, can cause group 1 PH [6–9, 13, 16–19]. Pulmonary veno-occlusive disease (PVOD) is another cause of group 1 pulmonary hypertension in the oncology population [3, 20]. Cancer therapies such as busulfan, cyclophosphamide, bleomycin, immune checkpoint inhibitors, and thoracic radiotherapy have been associated with lung toxicity and an increased risk of developing group 3 PH [6–8, 14, 19, 21]. Also, cancer patients can develop group 2 PH due to left ventricular dysfunction associated with oncologic treatment, valvular involvement associated with radiation, and progression of underlying coronary artery disease [1, 3, 22]. Cancer is a prothrombotic state, and patients with malignancies have a high risk of Venous thromboembolism (VTE), including pulmonary embolism and subsequent development of chronic thromboembolic pulmonary hypertension (CTEPH). Indeed, cancer is a prevalent comorbidity among patients with CTEPH [16, 17, 23]; inversely, a study of CTEPH patients reported a 17% prevalence of cancer, with breast and gastrointestinal cancers being the most common. Finally, group 5 PH has been described among patients with myeloproliferative neoplasms [18].

On the other hand, the risk of cancer was clearly higher in patients with PH compared to the general population [24]. During the first year after a PH diagnosis, the cancer risk was particularly high. However, PH was also associated with a long-term cancer risk. In a multicenter registry study of PH patients, 14.5% of PH patients developed cancer during follow-up [25, 26]. The pathophysiological mechanisms underlying this interrelationship remain unknown. This coexistence of cancer and PH complicates oncologic treatment and worsens the prognosis.

The PULAHYCA study was launched to address these challenges, specifically to assess whether initial triple therapy for pulmonary arterial hypertension would allow completing the specific oncologic treatment required by the patients. The group of patients included in the study had intermediate risk, and should, according to practice guidelines, receive specific dual therapy. In these patients, due to the need to initiate specific cancer treatment and the potential risk of PH progression due to a possible increase in pulmonary pressure and resistance, as well as the onset of heart failure with deterioration of right ventricular systolic function, treatment was escalated to an initial therapy with the addition of subcutaneous prostanoids. Over a follow-up period of 12-months, these patients were able to complete their oncologic treatment. If any change was required, it was not due to PH.

When analyzing the variables over the 12-month follow-up period, there no progression of PH, neither by an increase in PSAP, PAMP, PVR, nor by NT-proBNP values, or a deterioration in functional class on 6MWTs. In fact, there was an increase in the 6MWT and a decrease in NT-proBNP values. Of further note, many of the patients also experienced a decrease in PH risk categorization.

PULAHYCA is a promising study that demonstrates that PH patients requiring the initiation of specific oncologic therapy can achieve this through the association of initial PH therapy. This therapeutic association would allow completing oncologic therapy without PH progression, thus achieving remission or chronicity of the oncologic pathology.

Limitations

The PULAHYCA PILOT study has limitations mostly due to its small sample size and relatively short follow-up period, and a lack of a comparison group.

Future directions

In the future, it is imperative to conduct a prospective, randomized, multicenter study to validate our findings. This approach will allow for a more comprehensive evaluation of the role of initial PH therapy in cancer patients.

Conclusion

The PULAHYCA PILOT study demonstrates that treatment with subcutaneous treprostinil in intermediate-risk PH patients undergoing initial oncologic therapy enables completion of cancer treatment, leading to either remission or chronic disease control. Furthermore, beyond the oncologic benefit, patients exhibited improvements in both clinical status and objective markers of pulmonary hypertension severity.

Abbreviations

PAH

Pulmonary arterial hypertension

VEGFi

Vascular endothelial growth factor inhibitor

mPAP

Mean pulmonary artery pressure

PH

Pulmonary Hypertension

ESC

European Society of Cardiology

6MWT

Six-minute walk test

BNP

B-type natriuretic peptide

PVR

Pulmonary vascular resistance

WU

Woods Units

TKI

Tyrosine kinase inhibitor

PSAP

Pulmonary artery systolic pressure

PMAP

Pulmonary artery mean pressure

FC

Functional Class

PVOD

Pulmonary veno-occlusive disease

VTE

Venous thromboembolism

CTPH

Chronic thromboembolic pulmonary hypertension

Authors' contributions

VG and AD conducted the study and wrote and reviewed the document. DC, TLF and JH wrote and reviewed the document.

Funding

None.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.

Declarations

Competing interests

The authors declare no competing interests.