Following Chemotherapy: Serum Cytokine (Tumor Necrosis Factor,Interleukin-2, Interleukin-11), Immunoglobulin, Complement, Vascular EndothelialGrowth Factor Levels, and the Systemic Symptoms like Capillary LeakSyndrome

Introduction

Several problems such as myalgia, arthralgia, fever, dyspnea, generalized edema, andpleural effusion can occur in cancer patients. These symptoms and signs may appearmore frequently following up the chemotherapy treatment especially the first cycleof the first chemotherapy treatment. The pathophysiology of these symptoms and signshas not been discovered entirely yet. They are usually mild, but they may rarelyprogress to the severe stage that is known as “Systemic Capillary LeakSyndrome.”^1-3

Systemic capillary leak syndrome can be characterized by recurrent, reversibleepisodes of shock and peripheral edema with high mortality. It is seen equally inboth genders. This life-threatening syndrome is a sudden and unexplained leakage ofplasma into the tissues. The syndrome can follow the chemotherapy treatment,especially the first cycle of first chemotherapy treatment. However, the syndromecannot occur only in the following first cycle of the first chemotherapy treatment,but can also occur in the different periods of different chemotherapy treatmentprotocols and in patients with sepsis, angioedema, snake bite, and systemicanaphylaxis.^4-6

As it is known, this syndrome is not unique to the patients who take a chemotherapytreatment. They can appear in patients who have heart disease, lung disease, kidneydisease, and hypothyroidism.^5,6If a chemotherapy treatment contains paclitaxel, docetaxel, gemcitabine, orvinorelbine, these symptoms and signs can occur more often than the chemotherapytreatment not containing these drugs, but the pathophysiology is still notclear.^5-8 While the mechanism is unclear,it is thought that these drugs stimulate the synthesis and release of somecytokines. This altering of the balance of the cytokines causes changes in thebalance of acute phase proteins, complement, and immunoglobulins in serum.^4-6,9,10 Also, similar side effects canoccur during the usage of these cytokines for different indications.¹¹ Therefore, it is thought that these cytokines can play a key role in thepathophysiology of this syndrome and these symptoms and signs.^4-6 When deciding on the cytokinesto be studied, previous literature has been analyzed and it has been decided tostudy interleukin (IL)-2, IL-11, tumor necrosis factor alpha (TNF-α), and vascularendothelial growth factor (VEGF). These molecules have been previously accused thatthey cause similar side effects to symptoms and signs mentioned before duringimmunotherapy usage.^1,4-6,12,13

Although these symptoms and signs (generalized edema, hypotension, shortness ofbreath, fatigue, widespread muscle and joint pain, numbness, and skin rash) are notas severe as those in the systemic capillary leak syndrome, the clinical symptomsand signs are similar to each other. From this point, we hypothesized that thepathophysiology of the symptoms and signs are similar to the pathophysiology of thesystemic capillary leak syndrome. In this study, the relation between these symptomsand signs and the serum levels of the cytokine such as IL-2, IL-11, TNF-α, and VEGFwas investigated. It was also investigated the changes of the cytokine level and theresponse to the chemotherapy treatment.

Patients and Methods

A total of 44 cancer patients (26 males and 18 females) who had a tissue diagnosiswere recruited into this study. All of these cases did not previously receive anytreatment (chemotherapy/radiotherapy) for cancer disease. All of them were chosenfrom Ankara University Hospital, Department of Medical Oncology Clinic. Some caseswere selected from hospitalized patients and the other ones were selected fromambulatory cases who were resident in Ankara city. Cases who had heart, lung, liveror kidney disease, ongoing infection, any chronic inflammatory disease, autoimmunedisease, and used of steroid or any other drug that is affecting on immunoreactionwere excluded from the study.

The previous clinical studies and the clinical experiences have shown that thesesymptoms and signs can be seen after the second and third chemotherapy but theyoccur more common followed by the first chemotherapy.¹⁴ For this reason, in our study, considering the cost and the difficulty offollowing-up due to the prospective design, it was considered more appropriate toexamine only the first cycle of the first chemotherapy treatment where thesesymptoms and signs were most frequently observed according to the results of theseprevious studies. In addition, considering the cost again, IL-2, IL-11, TNF-α, andVEGF levels were measured only in the first-day serum samples. Since the bloodhalf-life of the cytokines is short, the blood samples were obtained in 24 h followof the chemotherapy. These blood samples were delivered to the nearest laboratory in20 min. Then, the serum samples were separated by centrifugation at 5000 r/min for5 min. These serum samples were placed in Eppendorf tube and stored at – °75 C.Hemoglobin, hematocrit, sedimentation, blood urea nitrogen, creatinine, totalprotein, albumin, aspartate aminotransferase (AST), alanine aminotransferase (ALT),gamma-glutamyltransferase (GGT), complement C3 and C4, immunoglobulins IgG, IgA,IgM, protein electrophoresis, spot urine protein, spot urine density, urineosmolarity, and serum osmolarity also measured before the chemotherapy treatment andon the first day after this treatment. Free-T3, free-T4, and TSH were also measuredbefore the treatment. All of these parameters were analyzed at Ankara UniversityMedical Faculty Hospital Laboratories. Besides the blood samples were obtained fromall participants, a questionnaire and a physical examination were alsosimultaneously applied to all participants to observe whether there are lowerextremity edema, weakness, shortness of breath, fever, rash-itch on the skin, voicemisery, cough, muscle, and joint pain.

All serum samples were removed from −75°C, and they were put in dry ice to betransported to the laboratory where the cytokines were studied. Then, all sampleswere allowed to stand at room temperature for melting before being analyzed. Thesamples were run in duplicate, and the results were evaluated aspicogram/milliliter. The measurements of VEGF, TNF, IL-2, and IL-11 were made usingthe enzyme-linked immunosorbent assay (ELISA) method on the device named “MedispecESR-200 Microplate Reader” which belongs to “IBM.”

Results

Serum cytokine levels, survey records, and physical examinations records wereanalyzed in 44 patients (26 males, 18 females; mean age: 52 ± 12 years, and agerange: 26-73 years). The study participants were heterogeneous for the diagnoses,treatment protocols, and age ranges. Patients with lung cancer (27 cases with 8small cells, 19 non-small cells; mean age: 57.7 ± 9.7 years, and age range:35-73 years) were in the majority of the study participants. The other cases (3males, 14 females; mean age: 47.2 ± 11.2 years, and age range: 26-63 years) wereconsisted of 11 operated breast cancer, 2 operated gastric carcinoma, 1 operatedcolon carcinoma, 1 operated ovarian cancer, 1 metastatic gastric carcinoma patientwho had neoadjuvant chemotherapy, 1 local advanced gastric, and 1 pancreaticcarcinoma. All the operated patients were under adjuvant chemotherapy medication.The demographic and clinical characteristics of the patients can be seen in Table 1. There was notumor tissue in the lungs of any patient except lung cancer cases (no lungmetastasis in any patient).

Table 1.

Demographic, clinical characteristics and the treatment protocols for allcases.

GenderPrimary tumor locationsStomachChemotherapeutic agents administered

Characteristics of patients	Number of patients (n = 44)	%
Age (min-max)	52 (26-73)
Male	26	59.1
Female	18	40.9
Lung	27	61.4
Breasta	11	25.0
Overa	1	2.3
Colona	1	2.3
Pancreas	1	2.3
Adjuvant	2	4.5
Neoadjuvant	1	2.3
PDGV group (total)b	21	47.7
Cisplatin + vinorelbine	7	15.9
Cisplatin + gemcitabine	3	6.9
Cisplatin + docetaxel	2	4.5
Cisplatin + paclitaxel	2	4.5
Carboplatin + paclitaxel	6	13.6
Paclitaxel	1	2.3
Other chemotherapy group (total)c	23	52.3
Cyclophosphamide + adriamycin (adjuvant)	5	11.3
Cyclophosphamide + adriamycin	4	9.1
Cyclophosphamide + adriamycin + 5-fluorouracil	2	4.6
Cisplatin + etoposide	8	18.1
Cisplatin + epirubicin	1	2.3
Cisplatin + 5-fluorouracil	1	2.3
Irinotecan + 5-fluorouracil	1	2.3
5-Fluorouracil (adjuvant)	1	2.3

Abbreviation: PDGV, paclitaxel, docetaxel, gemcitabine, orvinorelbine.

aPatients in complete remission following surgery who have undergoneadjuvant chemotherapy.

bPatients who have been administered any of the paclitaxel, docetaxel,gemcitabine, vinorelbine.

cPatients who have been administered chemotherapy drugs other thanpaclitaxel, docetaxel, gemcitabine, vinorelbine.

There were not enough cases to separate into the 5 groups as the patient who takespaclitaxel, docetaxel, gemcitabine, or vinorelbine and the other agents because thediagnoses and the treatment protocols of the patients were quite heterogeneous.Therefore, all the participants were divided into two groups. One of the groups(paclitaxel, docetaxel, gemcitabine, or vinorelbine [PDGV]) included patients whohad paclitaxel, docetaxel, gemcitabine, or vinorelbine therapy, which we expect mostsymptoms and signs would be developed in. The other group of patients were receivedthe chemotherapy drugs other than paclitaxel, docetaxel, gemcitabine, vinorelbine.According to the treatment protocols, there were 21 patients in PDGV treatment groupand 23 patients in the other treatment group. More detailed information about thetreatment procedures can be seen in more detail in Table 1.

There was no difference in both treatment groups for the sedimentation, serum proteinelectrophoresis, complement, and immunoglobulin levels. The decreasing of hematocritwas significant in the other treatment group (P = .013) while thehemoglobin levels were not changing (P = .157) in the same group(Table 2). When thesymptoms and signs were compared from the baseline to the first-day, regardless ofthe treatment protocols, there were significant differences between the baseline andthe first-day values of the body weight. The increase of the leg circumferences wassignificant in the other treatment group than the PDGV group. When it was evaluatedaccording to the treatment protocols, the systolic blood pressure was increased(P = .025) after taking the PDGV treatment while the diastolicblood pressure was not changed (P = .331) in the same group (Table 3). According to thePDGV group which was formed with the patients who had the paclitaxel, docetaxel,gemcitabine, and vinorelbine therapy, there was a more significant decrease in serumIL-11 levels after the chemotherapy treatment in the other treatment group(P = .006) (Table 4). However, there was no significantdifference in the VEGF, TNF, and IL-2 levels in the whole study group and the twotreatment subgroups (Table4).

Table 2.

Laboratory measurements before and after the chemotherapy treatment.

Complement (g/L)Immunoglobulin (g/L)Serum protein electrophoresis (%)

	The PDGV Treatment groupa (n = 21) X ± SD or Med (IQR)b		The other Treatment groupc (n = 23) X ± SD or Med (IQR)b		P1	P2
	Baseline	First day	Baseline	First day
Hemoglobin (g/dL)	12.3 ± 1.7	12 ± 1.8	12.3 ± 1.5	12.1 ± 1.6	.312	.157
Hematocrit	37.4 ± 5.1	36.5 ± 5.4	37.4 ± 4	36 ± 5	.245	.013d
Blood urea nitrogen (mg/dL)	19 ± 6.6	20.3 ± 6.1	17.9 ± 5.1	18.3 ± 5.9	.457	.820
Creatinine (mg/dL)	0.9 ± 0.2	0.9 ± 0.2	0.9 ± 0.2	0.8 ± 0.1	.695	.389
AST (UI/L)	20 ± 10	27 ± 13	21 (16-28)	22 (20-30)	.034d	.197
ALT (UI/L)	18 ± 14	23 ± 17	17 (14-34)	21 (15-34)	.136	.235
GGT (UI/L)	60 ± 58	60 ± 66	25 (17-41)	34 (20-100)	.652	.455
Total protein (mg/dL)	6.9 ± 0.4	7 ± 0.4	6.9 ± 0.6	6.9 ± 0.6	.567	.082
Albumin (mg/dL)	3.6 ± 0.4	3.6 ± 0.4	3.9 ± 0.3	3.8 ± 0.5	.794	.030d
Spot urine density	1017 ± 5	1014 ± 7	1014 ± 6	1014 ± 6	.349	1.00
Serum osmolality	283 ± 9	278 ± 5	281 ± 13	277 ± 6	.040d	.634
Urine osmolality	927 ± 335	953 ± 355	871 ± 403	890 ± 373	.643	.876
Sedimentation	56 ± 291	52 ± 33	41 ± 28	47 ± 38	.296	.148
C3	1.7 (1.3-133)	1.8 (1.4-131)	64 ± 73	54 ± 71	.551	.775
C4	0.4 (0.3-28)	0.4 (0.3-30)	12 ± 15	13 ± 17	.280	.785
G	18 (15-1084)	17 (14-1105)	563 ± 678	555 ± 62	.363	.858
A	3.3 (2.5-198)	4.1 (2.2-181)	95 ± 116	102 ± 122	.842	.622
M	1.2 (0.9-90)	1.6 (0.9-101)	56 ± 67	47 ± 62	.426	.774
Alb	48.4 ± 7	47.8 ± 6.3	51.4 ± 5.7	51.7 ± 6	.586	.353
α1	6.6 ± 1.8	6.7 ± 1.5	6 ± 2	5.8 ± 2.3	.196	.679
α2	15 ± 3	14.6 ± 3	13.1 ± 4.9	13 ± 5	.117	.887
β1	5.3 ± 0.8	5.4 ± 0.7	6.2 ± 0.8	5.9 ± 0.7	.266	.080
β2	6.2 ± 1	6.2 ± 0.9	6 ± 0.9	6.2 ± 0.8	.334	.453
γ	18.5 ± 4.3	19.2 ± 3.9	17.3 ± 3.8	17.3 ± 3.8	.249	.492

Abbreviations: ALT, alanine aminotransferase; AST, aspartateaminotransferase; GGT, gamma-glutamyltransferase; PDGV, paclitaxel,docetaxel, gemcitabine, or vinorelbine.

P₁ denotes difference before and after the treatment in thePDGV group. P₂ denotes difference before and after thetreatment in the other treatment group.

aPatients who have been administered any of the paclitaxel, docetaxel,gemcitabine, and vinorelbine.

bX ± SD: mean ± standard deviation. Med (IQR): median ± interquartilerange.

cPatients who have been administered chemotherapy drugs other thanpaclitaxel, docetaxel, gemcitabine, and vinorelbine.

dP-value < .05 was accepted as statisticallysignificant.

Table 3.

Clinical measurements and symptoms before and after the chemotherapytreatment.

Leg circumference (cm)Blood pressure (mmHg)

	The PDGV Treatment groupa (n = 21) X ± SDb		The other Treatment groupc (n = 23) X ± SD		P1	P2
	Baseline	First day	Baseline	First day
Body weight (kg)	68.4 ± 11.2	69.1 ± 11.4	70.6 ± 11.6	71.2 ± 12	.000d	.028d
Right	24 ± 3.3	24.5 ± 3.6	24.7 ± 1.8	25.2 ± 1.9	.125	.054
Left	24 ± 3.2	24.3 ± 3.5	24.5 ± 1.7	24.8 ± 1.8	.079	.038d
Systolic	109 ± 11	116 ± 14	121 ± 15	120 ± 16	.025d	.928
Diastolic	69 ± 8	71 ± 9	75 ± 9	75 ± 9	.331	1.00
Pulse (beat/min)	79 ± 13	80 ± 9	75 ± 9	75 ± 9	.519	.745
Weakness	—	1	—	1	—	—
Shortness of breath	—	4	—	4	—	—
Cough	—	3	—	4	—	—
Hoarseness	—	2	—	1	—	—
Skin rash	—	2	—	1	—	—
Muscle and joint pain	—	1	—	1	—	—

Abbreviation: PDGV, paclitaxel, docetaxel, gemcitabine, orvinorelbine.

P₁ denotes difference before and after the treatment in thePDGV group. P₂ denotes difference before and after thetreatment in the other treatment group.

No one had the fever, voice misery, and rash-itch on the skin before andafter receiving the chemotherapy.

aPatients who have been administered any of the paclitaxel, docetaxel,gemcitabine, vinorelbine.

bX ± SD: mean ± standard deviation.

cPatients who have been administered chemotherapy drugs other thanpaclitaxel, docetaxel, gemcitabine, and vinorelbine.

dP-value < .05 was accepted as statisticallysignificant.

Table 4.

Cytokine levels on the baseline and the first day following chemotherapy.

	The PDGV Treatment groupa (n = 21) X ± SD or Med (IQR)b		The other Treatment groupc (n = 23) X ± SD or Med (IQR)b		P1	P2
	Baseline	First Day	Baseline	First day
VEGF (pg/mL)	310 ± 185	309 ± 207	149 ± 146	146 ± 155	.968	.896
TNF (pg/mL)	14.3 (11.3-28.0)	20.5 (11.0-31.3)	19 ± 10	21 ± 11	.741	.421
IL-2 (pg/mL)	1.3 (0.1-27.6)	0.1 (0.1-13.6)	30 ± 46	25 ± 50	.422	.720
IL-11 (pg/mL)	26.8 (4.5-120.2)	45.6 (11.2-103.9)	68.1 (7.2-219.7)	24.2 (5.3-76.5)	.821	.006d

Abbreviations: IL, Interleukin; PDGV, paclitaxel, docetaxel, gemcitabine,or vinorelbine; TNF, tumor necrosis factor; VEGF, vascular endothelialgrowth factor.

P₁ denotes difference before and after the treatment in thePDGV group. P₂ denotes difference before and after thetreatment in the other treatment group.

aPatients who have been administered any of the paclitaxel, docetaxel,gemcitabine, and vinorelbine.

bX ± SD: Mean ± standard deviation. Med (IQR): median ± interquartilerange.

cPatients who have been administered chemotherapy drugs other thanpaclitaxel, docetaxel, gemcitabine, and vinorelbine.

dP-value < .05 was accepted as statisticallysignificant.

There was no statistical difference in both treatment groups for the weakness,shortness of breath, fever, rash-itch on the skin, voice misery, cough, muscle, andjoint pain. However, the skin rash and the hoarseness were appeared in 2 patients inthe PDGV group, and in 1 patient in the other treatment group. The shortness ofbreath was detected in 1 patient in PDGV group and in 4 patients in the othertreatment group. Also, after 10-12 hours the chemotherapy, 3 patients who receivedvinorelbine reported shortness of breath which it took half an hour andspontaneously recovered. It was detected cough in 2 patients who one of themreceived vinorelbine and the other one received gemcitabine in the PDGV group. Thecough was also detected in 4 patients in the other treatment group. When assessedthe muscle and joint pain, these symptoms were observed in 2 patients. One of themwas in the vinorelbine therapy subgroup of the PDGV group, and the other one was inthe other treatment group. They can be seen in Table 3.

It was not found any relation between the cytokine level changes and the chemotherapyresponse. Also, it was not seen any association between the developing signs andsymptoms and the response of the chemotherapy.

Discussion

In the present study, it was investigated the relationship between the serum cytokinelevels (VEGF, TNF-α, IL-2, and IL-11) and some symptoms and signs before and afterthe chemotherapy treatment. It was also investigated whether there is a relationshipbetween the changing of the cytokine levels, symptoms, and signs and thechemotherapy response in these cases. Previous chemotherapy experiences have beenshown that patients who were treated with paclitaxel, docetaxel, gemcitabine, orvinorelbine had the symptoms and signs such as a cough, flu-like symptoms, edema,and pain more frequently than the patients who were treated with otherchemotherapeutic agents.^15-18 Based on our clinicalobservation and the previous chemotherapy experiences, in this study, patients whotook the paclitaxel, docetaxel, gemcitabine, or vinorelbine were grouped into onegroup (PDGV group), and the other chemotherapy protocols were evaluated as “theother group.” However, no patients with clinical symptoms and signs of capillaryescape syndrome were found in neither group. Since it is known that this syndrome israrely observed, the symptoms and signs suspected of being similar to thepathophysiology were questioned, but there was also no difference between the groupsin terms of symptoms and signs.^15,17,19

Amoura et al¹⁶, and Kawabe et al²⁰ evaluated 69 patients with systemic capillary leak syndrome, retrospectively.They detected an elevation of hemoglobin, hematocrit, blood urea nitrogen,creatinine, and monoclonal IgG levels while a decreased of serum total protein andalbumin levels without proteinuria, and also the changes in serum complement C3 andC4 levels (increased in some cases, decreased in some other cases).^11,16,20 In addition,Amoura et al¹⁶ reported that 4 out of 13 patients had upper respiratory tract infectionhistory in 2 weeks before receiving the chemotherapy treatment.¹⁶ In our study, it was not questioned whether the participants had anyinfection before the treatment period. We asked whether there was any infection atthat moment. If there was an infection at that moment, the patient was not enrolledin the study. We detected also decrease in hematocrit, especially in the othertreatment group. The fell in hematocrit could be based on the serum dilution due tothe water retention. Increased the body weight and the leg circumferences were alsosupporting the water retention hypothesis. It was not found a significant change inother parameters in our study.

The relationship between IL-11 and the prognosis of patients with various cancershave been investigated in several studies. One of them was carried out by Berry et al.²¹ They observed that tumor cells which metastasized to bone in patients withbreast cancer were more likely to overexpressed IL-11. And this overexpressed IL-11was a poor prognostic indicator. In our study, there was no significant change inserum IL-11 levels before and after the chemotherapy in PDGV group(P = .821) while there was a significant decrease in the othertreatment arm (P = .006). We could not find any relation betweenthe prognosis and levels of IL-11 in both groups in 8 months. This result in ourstudy is thought to be due to the short follow-up period and the low number ofcases. As with other cytokines, there was also no correlation between serum IL-11levels and the symptoms of the patients. Maybe the reason was that 15 of 44 patients(34% of all patients) received adjuvant chemotherapy in our patient group, while therecent studies have stated that serum cytokine levels correlate with tumorburden.^22-29 Since the number of patientswas low, and 34% of all patients received adjuvant chemotherapy, it could not bedetected any significant difference in serum IL-2, TNF, VEGF levels, and accordinglythe symptoms.

No relationship between the serum cytokine levels and the symptoms and signs afterthe chemotherapy treatments arose from the short serum half-lives ofcytokines.^4,30,31 Therefore, we could not catch the peak of serum cytokineslevels at the 24th hour of the treatment. We observed “shortness of breath thatdevelops after 12 h of chemotherapy and lasts for about half an hour” in threepatients who received vinorelbine in the PDGV group. That can be explained by theshort serum half-lives of these cytokines. In this respect, for an objectiveassessment, the serum cytokine levels in those patients may need to be assessed withserum samples taken every 15 min after treatment. It is clear that the applicationof this working order would not be suitable for a clinical trial on humans.

There was also no correlation between changes in serum cytokine levels, symptoms andsigns, and response to the chemotherapy treatment protocols in our study. Thisresult can be dependent on three parameters: the heterogeneous patient group for thecancer types, the malign cell burdens, and the heterogeneous treatment protocols.When it was looked at the previous studies, if a study group was composed ofheterogeneously patient groups in terms of these parameters, it was reported thatthere is no relationship between the changes in serum cytokine levels and theseparameters, and vice versa.^32,33 It is seen that the low number of patients was in our study, aswell as the heterogeneous patient group for cancer type and treatment protocols. Thefairly high standard deviation values of serum VEGF, TNF-α, IL-2, and IL-11 were themost important indicator that patient heterogeneity greatly influenced the resultsof our study. The reason for the heterogeneity of our patient group was that allpatients were chosen randomly at the outpatient and inpatient clinics.

VEGF level in circulation is consisted of VEGF released from tumor tissue, as well asVEGF released from platelets or leukocytes during normal blood clotting. One of theimportant points to note is that the majority of the previous studies evaluated theVEGF levels in frozen tumor tissue, tumor cytosol, or paraffin embedded tumortissues^34-37 not in the serum samples. Ascan be expected, VEGF level is the higher in the hypoxic tumor tissue and itsneighboring tissues than the serum. However, we measured the VEGF levels in serumsamples in our study. If a study in which VEGF level was measured in serum sample,similar to our study, the increased in circulating VEGF levels was particularlyassociated with large tumor burden and metastatic disease.^23,28,29,38 All of the breast cancerpatients in our study received adjuvant chemotherapy (VEGF-releasing tumor tissue istheoretically absent). Therefore, it was not surprising that our patients serum VEGFlevels were lower than the similar previous studies.^{23,28,29,34-38} There was also no significantchanges in serum VEGF levels before and 24 h after the chemotherapy treatment.

When it is looked at the previous publications about the levels of complement andimmunoglobulin in cancer patients, the pre-chemotherapy treatment period has beenevaluated to find out whether there is a relation between these marker levels andthe prognosis. One of the exception of these previous studies, Tsavaris et al¹⁹ evaluated levels of complement and immunoglobulin in 100 colorectal cancerpatients at pre and post period of the receiving chemotherapy treatment. Theydetected increasing IgG and IgM levels before the chemotherapy treatment wascorrelated with prolonged life-span.¹⁹ In our study, we evaluated the differences in Ig and complement levels beforeand 24 h after the first cycle of the first chemotherapy treatment. In our study,there was no difference between immunoglobulin and complement levels inpre-chemotherapy and post-chemotherapy treatment periods, either in the lung cancergroup or in the other group which includes the patients with breast cancer. Inaddition, there was no correlation between Ig and complement levels and prognosis.The patient group who had adjuvant chemotherapy treatment (who had no tumor tissueis theoretically) was not considered responsible for this result, because 29patients (65.9%) who had neoadjuvant treatment had also the same result.

Previous studies have shown that there is a triad becoming of hypotension,hemoconcentration, and serum hypoalbuminemia in the systemic capillary leak syndrome.⁴ We did not detect any systemic capillary leak syndrome case in our patientgroup. After the treatment, we identified some symptoms and signs only. However, wehypothesized that the pathophysiology of the symptoms and signs (generalized edema,hypotension, shortness of breath, fatigue, widespread muscle and joint pain,numbness, and skin rash) can have similar pathophysiology of this syndrome. We lookat this aspect, the differences between the results of our study and the previousstudies may arose the characteristics of the patient groups (cancer type, treatmentprotocols, and the tumor burden).^4-6 In our study, the systolic bloodpressure was increased (P = .032) after taking the treatment inPDGV group while the diastolic blood pressure was not changed(P = .286) in the same group. The albumin level, and serum andurine osmolarity were not changed before and after the treatment in both groups.

In the present study, we could not determined any correlation between the serumcytokine levels, symptoms and signs, chemotherapy response, and chemotherapeuticdrugs which is thought to be responsible for capillary leak follow-up thechemotherapy treatment. We also did not detect any systemic capillary leak syndromebecause the syndrome is appeared very rare and our case number was low. We did notdetect any significant change of the serum IL-2, TNF, and VEGF levels before andafter the treatment. The result could be dependent on the small sample size and theshort half-life of cytokine. We collected the serum samples before and 24 h afterthe chemotherapy treatment, so we could not catch the peak-time of thesecytokines.

Conclusions

The topic is a current topic between the clinicians. These symptoms andlife-threatening syndrome is a sudden and unexplained leakage of plasma into thetissues. It can appear in patients who have heart disease, lung disease, kidneydisease, and hypothyroidism. It can appear in patients who take a chemotherapytreatment, too. If a chemotherapy treatment contains paclitaxel, docetaxel,gemcitabine, or vinorelbine, these symptoms and signs can occur more often than thechemotherapy treatment not containing these drugs, but the pathophysiology is stillnot clear. In this study, there was no association between edema, dyspnea, cough,flu-like symptoms, and signs suggesting the cytokine effect associated with thechemotherapy drugs administered. According to the group receiving PDGV treatment,there was a significant decrease in IL-11 levels (P = .006) in theother treatment group, but no correlation was found between the drugs applied andthe mentioned symptoms, the chemotherapeutic response, the level of serum TNF, IL-2,L-11, and VEGF. The result could be dependent on the small sample size and the shorthalf-life of cytokine. However, this study can raise awareness about this topic, andit can lead to larger and well-planned studies.