A Phase IV Clinical Trial of Patients with Solid Tumors Receiving Lenograstim as Primary Prophylaxis for Chemotherapy-Induced Neutropenia, in a Docetaxel-Based Regimen

Docetaxel-based chemotherapy regimens have substantially improved survival and recurrence rates for cancer patients. Safety profile of docetaxel regimens includes toxicities, particularly a high risk of neutropenia and febrile neutropenia. Granotax was a prospective, open label, multicentre, national phase IV study that evaluated the incidence and severity of neutropenia in adult patients with solid tumors being treated with a docetaxel-based regimen while receiving the GCSF lenograstim. Among the 394 enrolled patients the incidence of grade 3-4 neutropenia was 16.2% and of febrile neutropenia was 1.5%, far lower than the reported 85–100% and 30–40% incidence without G-CSFs. A total of 68 patients (17.3%) were reported to have experienced at least one grade 3-4 adverse event during the study. Two (0.5%) patients and 32 (8.1%) patients had dose delayed due to febrile neutropenia and neutropenia, respectively. Four (1.0%) patients and 32 (8.1%) patients had a dose changed due to febrile neutropenia and neutropenia, respectively. The low incidence of adverse effects and chemotherapy dose changes, delays, and withdrawals supports the use of lenograstim as effective primary prophylaxis in South African patients being treated with a docetaxel-based regimen. Furthermore, lenograstim may increase the patient’s exposure to chemotherapy allowing patients to receive optimal dosing and duration of treatment, benefitting survival.


Introduction
South Africa is ranked 50th on the World Cancer Research Fund's list of countries with the highest cancer prevalence [1] and has recently been predicted to have a 78% increase in cancer cases by 2030 [2].Breast cancer is the number one cancer diagnosed amongst South African women with a 1 in 29 lifetime risk [2,3], while prostate cancer is the most prevalent in men [4].Nevertheless, treatment options have substantially improved survival rates.Systemic adjuvant chemotherapy with anthracycline-and taxane-containing regimens has become the standard first line treatment for early and metastatic breast cancer [5], with large phase III randomized trials showing extremely high long-term disease-free survival and overall survival rates (resp., 80% and 90% at 5 years and 70% and 80% at 8 years) [6].Indeed, a recent meta-analysis of data from 44,000 early breast cancer patients showed that the addition of a taxane such as docetaxel in anthracycline regimens reduces mortality by an average of ∼33%.Furthermore, this is largely independent of age, nodal status, tumor diameter or differentiation, estrogen receptor status, or tamoxifen use [7].
These improvements in outcome are very welcome, yet they do have associated substantial toxicities, especially a moderate-to-high risk of neutropenia or febrile neutropenia (FN) [8].Such adverse effects are serious and can be lifethreatening and commonly occur during the initial cycles of cytotoxic therapy [8][9][10].Furthermore, they can lead to delays and dose reductions in chemotherapy treatment, thereby potentially compromising the efficacy of chemotherapy and, consequently, patient outcome [10].In fact, reducing the planned dose intensity of systemic adjuvant chemotherapy regimens by as little as 15% has been shown to significantly reduce time to progression and overall survival rates in women with metastatic breast cancer [5].
There is strong and consistent clinical evidence to show that granulocyte-colony stimulating factors (G-CSFs) reduce the risk of chemotherapy-induced neutropenia and therefore complicated neutropenia and can be used to maintain chemotherapy at the desired dose intensity or density and minimize delays in treatment [11].G-CSFs have been shown to reduce overall mortality risk [8,11], reduce the incidence of other adverse events (grade 2 or greater anaemia, asthenia, anorexia, myalgia, nail disorders, and oral mucositis) associated with docetaxel-based chemotherapy regimens, and increase health related quality of life and consequently treatment compliance [8,12].Based on this evidence, guidelines published by the American Society of Clinical Oncology and the European Organisation for Research and Treatment of Cancer state that when the overall risk of FN is 20% or greater, especially on "dose dense" regimens, primary prophylaxis with G-CSFs is justified [10,13].
The current study is the first to focus on South African patients in a real life setting.The primary objective was to evaluate the incidence and severity of neutropenia in those being treated for solid tumors with a docetaxel-based regimen when the G-CSF, lenograstim, is used as a primary prophylaxis for chemotherapy-induced neutropenia.Secondary objectives included evaluating similarly the incidence and severity of FN (with or without antibiotics).Further nonhematological secondary objectives included evaluating the incidence and severity of asthenia, anorexia, myalgia, nail changes, and oral mucositis adverse events and recording neutropenia/FN associated days in hospital, infections, use of anti-infectives, and chemotherapy dose changes, withdrawals, or treatment delays.

Methods
Granotax (NCT01107756) was a prospective, open label, national multicentre, phase IV postmarketing study that evaluated the incidence and severity of neutropenia in adult patients with solid tumors being treated with a docetaxelbased regimen while receiving the G-CSF lenograstim.

Patients.
The study protocol was approved by the independent institutional review boards of each site and a written informed consent was obtained from patients before study entry, in accordance with the Declaration of Helsinki [14].Adult patients (≥21 years) were enrolled in the survey from 27 medical centers across South Africa.Patients with a histological diagnosis of breast cancer, non-small cell lung cancer (NSCLC), ovarian cancer, prostate cancer, or head and neck cancer to be treated with a docetaxel-based chemotherapy regimen and who had not previously been treated on a docetaxel-based chemotherapy regimen were eligible for inclusion in the study.Patients with severe impairment in biochemistry or bone marrow function, known hypersensitivity to lenograstim, its constituents, docetaxel or polysorbate 80, or taking contraindicated drugs were excluded from the study.Patients who were concurrently being treated with radiotherapy were also excluded.The planned sample size was 400-500 patients.

Treatment.
All patients enrolled in the study were treated on a docetaxel-based chemotherapy regimen (either docetaxel alone or in combination).Lenograstim was to be administered with every cycle of chemotherapy.Treatments were given in accordance with the physicians' current practice, clinical guidelines, and ethical considerations, with guidance from the prescribing information in South Africa, according to Medicines Control Council (MCC) registration.Patients were monitored according to the study protocol until the scheduled date of study completion or up to recovery or stabilization of a followed-up AE, whichever came last.The patient or physician could decide to withdraw from the treatment at any time for any reason.

Efficacy Assessments.
Since the primary criteria were safety parameters, these events were recorded as outcomes as well as adverse events.All adverse events were graded according to the CTCAE version 4.03 classification system.Specifically, the incidence and severity of neutropenia, FN, anaemia, asthenia, myalgia, oral mucositis, and nail changes were recorded from the first treatment dose up until 30 to 90 days following the last treatment visit.Haematological tests were performed according to the treating physician's usual practice and values were collected and recorded in the case report form (CRF).

Safety Assessments.
Safety measurements collected throughout the study included all other adverse events (excluding the primary and secondary criteria of the study), clinical laboratory assessments (hematology and clinical chemistry), and physical examination findings.All these measurements were performed and collected according to the standard of practice at the investigator site.Records were made of the number of neutropenia/FN associated stays in hospital, infections, use of anti-infectives, and chemotherapy dose changes, withdrawals, and treatment delays.

Statistical Analysis.
Data from all the participating centers in South Africa were combined and treated as one dataset for the purposes of the analysis.The statistical analysis of the survey was of a descriptive nature where continuous variables were summarized by mean, median, standard deviation, and minimum and maximum values and discrete variables were summarized by frequencies and percentages.
All analyses were carried out on SAS, Release 9.2, run under Microsoft Windows for a personal computer.The percentage is calculated out of the 394, the total number of patients in the study's cohort for sex, age, ECOG status, and cancer type.The following combination concurrent regimens were most commonly used: docetaxel + cyclophosphamide (TC), docetaxel plus carboplatin (TCb), and docetaxel, cisplatin + 5FU (DCF).

3
The median dosage of docetaxel given in these regimens was 75 mg/m 2 on a 3-weekly schedule.
The following combination sequential regimens were commonly used: doxorubicin, cyclophosphamide followed by docetaxel (AC-T);5 FU, epirubicin, cyclophosphamide followed by docetaxel (FEC-T); doxorubicin, cyclophosphamide followed by docetaxel and trastuzumab (AC-T + H).The percentage is calculated out of the 394, the total number of patients in the study's cohort.
The median dose of docetaxel used in the combination sequential regimen was 100 mg/m 2 on a 3-weekly schedule.
Docetaxel as a single agent was given at a mean dosage level of 80 mg/m 2 on a 3-weekly schedule.
The median number of lenograstim vials used per patient per cycle was 5.0.49 (12.4%)patients had a recorded change in the lenograstim treatment.Changes in lenograstim treatment were recorded as dose reductions and dose delays, as well as an increase in the dose compared with the preceding cycle of treatment.The reasons for these changes were recorded as asthenia (0.25%), myalgia (1.0%), neutropenia (3.3%), infections other than febrile neutropenia (0.25%), febrile neutropenia (0.51%), other adverse events (0.76%), and other (7.4%).Some patients reported multiple reasons for treatment changes.
Neutropenia, febrile neutropenia, and other secondary outcome measures are listed in Table 2.

Safety Outcomes.
The safety data reported here does not include the primary and secondary objectives related adverse events of neutropenia, FN, asthenia, anorexia, myalgia, oral mucositis, or nail changes.378 (95.9%) patients experienced at least one adverse event (all grades), and 68 (17.3%) patients experienced at least one grade 3-4 adverse event (Table 3).The percentage is calculated out of the 394, the total number of patients in the study's cohort.Adverse effects are listed which occurred in more than 10 patients and with at least one reported grade 3-5 event.
Two patients died during study treatment (within 30 days after the last lenograstim administration): one patient with gastric cancer treated with docetaxel/cisplatin/5-flurouracil died from embolism considered not related to lenograstim and chemotherapy.The patient was diagnosed with a massive deep vein thrombosis (DVT) in the left arm involving the jugular, axillary, subclavian, and brachial veins.This extensive DVT caused an embolism.The investigator gave the following explanations as possible causes for the SAE: recent insertion of a port and paraneoplastic syndrome.Causality is sometimes difficult to determine, and it is reported according to the treating physician's impression on causality.One patient with prostate cancer treated with docetaxel single agent died from intracranial hemorrhage considered as related to lenograstim and chemotherapy.

Chemotherapy Treatment Delays, Changes
, and Withdrawals.85 (21.6%) patients were reported to have had at least one treatment delay in their chemotherapy regimen during the course of the study.The most common reason was neutropenia, with an incidence of 8.1%.Delay due to FN was reported in 0.5% of patients.When considering dose changes in chemotherapy treatment, a similar pattern was observed in the 144 (36.5%) patients who had at least one modification made to their chemotherapy dose during the study (Table 4).
Out of the 80 (20.3%) patients who did not complete their prescribed regimen, most withdrawals were due to disease progression, withdrawing consent from the study, and adverse events other than neutropenia, FN, asthenia, anorexia, myalgia, oral mucositis, or nail changes.Among the 13 patients who did not complete planned treatment due to death, 2 occurred within 30 days after last lenograstim administration.21 patients (5.3%) of the total cohort had lenograstim-associated reasons for discontinuing treatment, with one death but a low incidence of adverse events and no toxicities (Tables 5 and 6 ).The percentage is calculated out of the 394, the total number of patients in the study's cohort.A patient may have more than one reason recorded for change or delay in treatment.

Discussion
The primary outcome of the Granotax study found the incidence of clinically important grade 3-4 neutropenia to be 16.2% in adult patients being treated for a solid tumor with a docetaxel-based chemotherapy regimen and using lenograstim as primary prophylaxis.The study mainly included patients with breast cancer who were indicated for adjuvant therapy.In the BCIRG001 study conducted in 1491 women with node-positive breast cancer patients treated with adjuvant TAC versus FAC without the use of primary prophylactic G-CSF, the incidence of grade 3 or 4 neutropenia was 65.5% and the incidence of febrile neutropenia was 24.7% in treatment group treated with TAC [15].Another study conducted in 1059 patients with high risk node-negative breast cancer showed that the addition of primary prophylactic granulocyte-colony stimulating factor in breast cancer patients treated with docetaxel, doxorubicin, and cyclophosphamide (TAC) decreased the incidence of neutropenic fever from 27.2% to 7.5% [12].The present study's results thus clearly show a relatively low incidence of febrile neutropenia.
It could be argued that since this is not a systematic clinical trial but rather a study in real-life clinical settings, where monitoring is carried out according to the physician's normal practices, this low incidence of isolated neutropenia could not only be due to lenograstim use, but also be influenced by the lack of rigidly scheduled weekly tests leading to underreporting of neutropenia.However, more clinically important is the incidence of complicated neutropenia, where diagnosis is based on symptomatic presentation rather than requiring systematic hematological testing.In the Granotax study, FN was reported in 1.5% of patients and neutropenic infections in 1.8% of patients, rates far below the 30-40% incidence rate of complicated neutropenia usually reported with docetaxel-based chemotherapy regimens [13].
For example, a multicenter phase III study on 528 high risk node-negative breast cancer patients treated with adjuvant docetaxel-based regimen showed a reduced FN incidence rate from 27%, where only some patients were treated with reactive G-CSF (filgrastim or lenograstim) prophylaxis, to 7.5% with G-CSF primary prophylaxis for all patients [12].The even lower rate in the present study may be due to a more widespread variability of baseline cancer grades and types.This study also showed a reduced incidence of nonneutropenia adverse events (secondary efficacy outcomes) with primary lenograstim prophylaxis, supporting earlier studies also showing reductions with G-CSFs [12].
An important result in the Granotax study was that neutropenia was the number one cause of chemotherapy treatment changes and delays, at a rate of 8.1% for each measure.Yet this is a relatively low rate when considering the results of a recent meta-analysis, which cites significant dose reductions and delays as common clinical practice in the management of patients with primary breast cancer, where febrile neutropenia and changes in liver enzymes were the major causes for dose reductions and delays [16].An even more alarming picture might be observed in patients with metastatic breast cancer, where dose delays and reductions are common methods of reducing the toxicity and maintaining the quality of life but reduce overall survival [16].It follows that the use of prophylactic lenograstim not only may increase the patient's exposure to the chemotherapy and allow for optimal dosing and duration of treatment, but also have an impact on important patient outcomes.
In the Granotax study, a total of 68 patients (17.3%) were reported to have experienced at least one grade 3-4 adverse event during the study, and 1 (0.25%) died from intracranial hemorrhage considered as related to chemotherapy and lenograstim.Only 4.3% of patients withdrew from treatment due to adverse events.Moreover, not one of these withdrawals was due to isolated or complicated neutropenia, despite a hospitalization rate of 5.3% for isolated neutropenia and 1.3% for complicated neutropenia.Overall, the rate of treatment withdrawals was 20%.Only 1.5% of patients withdrew treatment due to lenograstim related adverse events.This suggests good tolerability to lenograstim.

Overall Conclusion
The low incidence of isolated and complicated neutropenia reported in Granotax study may indicate support for the routine use of G-CSFs, such as lenograstim, in cancer patients on a docetaxel-based regimen.The Granotax study also confirms the safety of lenograstim in South African patients.The results from the Granotax study are hoped to contribute to the rational and appropriate use of G-CSF as primary prophylaxis in patients being treated with a docetaxel-based chemotherapy regimen in South Africa.oncology at Sanofi South Africa.The other authors declared no conflict of interests.

3. 5 .
Neutropenia-Associated Complications.Other secondary outcome measures included recording the number of infections, use of anti-infectives, and hospitalization associated

Table 1 :
Patient and cancer baseline characteristics.

Table 2 :
Incidence of neutropenia, febrile neutropenia, and other adverse effects.

Table 3 :
Adverse effects not related to primary and secondary objectives, regardless relationship with chemotherapy.

Table 4 :
Reasons for docetaxel-based chemotherapy dose delays and changes.

Table 5 :
Reasons for discontinuing treatment.

Table 6 :
Causes of death in 13 patients.