Carboplatin, Paclitaxel and Gemcitabine Hydrochloride With or Without Bevacizumab After Surgery in Treating Patients With Recurrent Ovarian, Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

Study Overview
=================
Brief Summary
-----------------
This randomized phase III trial studies carboplatin, paclitaxel and gemcitabine hydrochloride when given together with or without bevacizumab after surgery to see how well it works in treating patients with ovarian, epithelial, primary peritoneal, or fallopian tube cancer that has come back. Drugs used in chemotherapy, such as carboplatin, paclitaxel and gemcitabine hydrochloride work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as bevacizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether combination chemotherapy is more effective when given with or without bevacizumab after surgery in treating patients with ovarian, epithelial, primary peritoneal, or fallopian tube cancer.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine if surgical secondary cytoreduction in addition to adjuvant chemotherapy increases the duration of overall survival in patients with recurrent platinum sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer. II. To determine if the addition of bevacizumab to the second-line and maintenance phases of treatment increases the duration of overall survival relative to second-line paclitaxel and carboplatin alone in patients with recurrent platinum sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer. SECONDARY OBJECTIVES: I. To determine if the addition of bevacizumab to the second-line and maintenance phase of treatment increases the duration of progression-free survival relative to second-line paclitaxel and carboplatin alone in patients with recurrent platinum sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer. II. To prospectively determine the incidence of carboplatin and paclitaxel hypersensitivity in these patients undergoing retreatment with both agents as first recurrence therapy. III. To determine if surgical secondary cytoreduction in addition to adjuvant chemotherapy increases quality of life (QOL) in patients with recurrent platinum-sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer, as measured by the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) trial outcome index and Rand Short Form (SF)-36 physical functioning scale. IV. To determine if the addition of bevacizumab to the second-line and maintenance phases of treatment increases QOL relative to second-line paclitaxel and carboplatin alone in patients with recurrent platinum-sensitive epithelial ovarian, peritoneal primary or fallopian tube cancer. TRANSLATIONAL RESEARCH OBJECTIVES: I. To define molecular and biochemical profiles associated with the duration of progression-free survival in platinum-sensitive recurrent ovarian, peritoneal primary or fallopian tube carcinoma treated with combination chemotherapy with or without bevacizumab followed with or without maintenance bevacizumab therapy in the presence or absence of secondary surgical cytoreduction. II. To identify molecular determinants that predict sensitivity or resistance to carboplatin and paclitaxel with or without bevacizumab followed with or without maintenance bevacizumab therapy. III. To bank deoxyribonucleic acid (DNA) from whole blood for research and evaluate the association between single nucleotide polymorphisms (SNPs) and measures of clinical outcome including overall survival, progression-free survival and adverse events. OUTLINE: Patients are assigned to 1 of 4 treatment groups. Patients who are not candidates for surgical cytoreduction (i.e., those for whom complete cytoreduction in the estimation of the investigator is impossible or a medical infirmity precludes exploration and debulking) are eligible to receive chemotherapy after randomization. Patients who are eligible for surgery undergo abdominal exploration with cytoreduction. Patients are then randomized to 1 of 4 treatment arms. ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours or docetaxel IV over 1 hour and carboplatin IV over 60 minutes on day 1. ARM II: Patients receive chemotherapy as in Arm I and bevacizumab IV over 30-90 minutes on day 1. ARM III: Patients receive gemcitabine hydrochloride IV over 60 minutes on days 1 and 8 and carboplatin as in Arm I. ARM IV: Patients receive gemcitabine hydrochloride IV as in Arm III, bevacizumab IV and carboplatin IV as in Arm II. In all arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with measurable disease achieving a clinical response (CR) receive 6-8 courses of therapy. Patients with stable disease or partial regression receive a maximum of 8 courses. Patients without measurable lesions as determined by a computed tomography (CT) scan prior to initiating study treatment continue therapy for 6 courses or, if cancer antigen (CA)-125 normalizes, for 2 courses beyond CA-125 normalization, whichever is greater. Patients in Arm II then receive a maintenance regimen comprising bevacizumab IV over 30-90 minutes. Treatment with bevacizumab alone repeats every 3 weeks in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly for 5 years.

Official Title
-----------------
A Phase III Randomized Controlled Clinical Trial of Carboplatin and Paclitaxel (or Gemcitabine) Alone or in Combination With Bevacizumab (NSC #704865) Followed by Bevacizumab and Secondary Cytoreductive Surgery in Platinum-Sensitive, Recurrent Ovarian, Peritoneal Primary and Fallopian Tube Cancer. NCI-Supplied Agents: Bevacizumab (NSC #704865)

Conditions
-----------------
Clear Cell Adenocarcinoma, Fallopian Tube Clear Cell Adenocarcinoma, Fallopian Tube Endometrioid Adenocarcinoma, Fallopian Tube Mucinous Adenocarcinoma, Fallopian Tube Serous Adenocarcinoma, Fallopian Tube Transitional Cell Carcinoma, Fallopian Tube Undifferentiated Carcinoma, Mucinous Adenocarcinoma, Ovarian Brenner Tumor, Ovarian Clear Cell Adenocarcinofibroma, Ovarian Clear Cell Adenocarcinoma, Ovarian Endometrioid Adenocarcinoma, Ovarian Seromucinous Carcinoma, Ovarian Serous Adenocarcinoma, Ovarian Transitional Cell Carcinoma, Ovarian Undifferentiated Carcinoma, Primary Peritoneal Clear Cell Adenocarcinoma, Primary Peritoneal Endometrioid Adenocarcinoma, Primary Peritoneal Serous Adenocarcinoma, Primary Peritoneal Transitional Cell Carcinoma, Primary Peritoneal Undifferentiated Carcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Ovarian Carcinoma, Recurrent Primary Peritoneal Carcinoma, Undifferentiated Carcinoma

Intervention / Treatment
-----------------
* Biological: Bevacizumab
* Drug: Carboplatin
* Drug: Docetaxel
* Drug: Gemcitabine Hydrochloride
* Other: Laboratory Biomarker Analysis
* Drug: Paclitaxel
* Other: Quality-of-Life Assessment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients enrolled after August 28, 2011 must be candidates for cytoreductive surgery and consent to have their surgical treatment determined by randomization Patients must have histologic diagnosis of epithelial ovarian carcinoma, peritoneal primary or fallopian tube carcinoma, which is now recurrent Patients with the following histologic epithelial cell types are eligible: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's tumor, or adenocarcinoma not otherwise specified (N.O.S.) Patients must have had a complete response to front-line platinum-taxane therapy (at least three cycles) A complete response to front-line chemotherapy must include: negative physical exam, negative pelvic exam and normalization of CA125, if elevated at baseline; although not required, any radiographic assessment of disease status (e.g. CT, magnetic resonance imaging [MRI], positron emission tomography [PET]/CT, etc) obtained following the completion of primary therapy should be considered negative for disease All patients must have also had a treatment-free interval without clinical evidence of progressive disease of at least 6 months from completion of front-line chemotherapy (both platinum and taxane); front-line therapy may have included a biologic agent (i.e. bevacizumab) Front-line treatment may include maintenance therapy following complete clinical or pathological response; however, maintenance cytotoxic chemotherapy must be discontinued for a minimum of 6 months prior to documentation of recurrent disease; patients receiving maintenance biological therapy or hormonal therapy are ELIGIBLE provided their recurrence is documented more than 6 months from primary cytotoxic chemotherapy completion (includes maintenance chemotherapy) AND a minimum 4 weeks has elapsed since their last infusion of biological therapy Patients must have clinically evident recurrent disease for the purpose of this study Measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST]) is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded); each lesion must be more than or equal to 20 mm when measured by conventional techniques, MRI or CT, or more than or equal to 10 mm when measured by spiral CT Absolute neutrophil count (ANC) greater than or equal to 1,500/mm^3, equivalent to Common Toxicity Criteria for Adverse Events version (v)4.0 (CTCAE) grade 1 Platelets greater than or equal to 100,000/mm^3 (CTCAE grade 0-1) Creatinine (non-isotope dilution mass spectrometry [IDMS]) =< 1.5 x institutional upper limit normal (ULN), CTCAE grade 1 Total bilirubin =< 1.5 ULN (CTCAE grade 1) Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST) =< 2.5 times the upper limit of normal in the absence of liver metastasis; SGOT/AST < 5.0 times ULN in the presence of liver metastasis Alkaline phosphatase =< 2.5 times the upper limit of normal in the absence of liver metastasis; alkaline phosphatase < 5.0 times ULN in the presence of liver metastasis This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients must have a urine protein-to-creatinine ratio (UPCR) < 1.0 mg/dL This eligibility criterion does not apply to patients enrolled after August 28, 2011; patients who are not candidates for surgical cytoreduction are eligible for the chemotherapy randomization; patients are not considered candidates for surgical cytoreduction if complete cytoreduction in the estimation of the investigator is impossible or a medical infirmity precludes exploration and debulking Patients must have met the pre-entry requirements as specified Patients must have signed an approved informed consent and authorization permitting release of personal health information Patients must have a Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2 Exclusion Criteria: Patients who have received more than one previous regimen of chemotherapy (maintenance is not considered a second regimen) Patients receiving concurrent immunotherapy, or radiotherapy Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded Patients whom have already undergone secondary cytoreduction for recurrent disease are excluded Patients with a prior histologic diagnosis of borderline, low malignant potential (grade 0) epithelial carcinoma that was surgically resected and who subsequently developed an unrelated, new invasive epithelial ovarian or peritoneal primary cancer are eligible provided that they meet the criteria listed above Patients who require parenteral hydration or nutrition and have evidence of partial bowel obstruction or perforation Patients who have received prior chemotherapy for any abdominal or pelvic tumor (other than ovarian, fallopian tube, and primary peritoneal) are excluded Patients with synchronous primary endometrial cancer, or a past history of primary endometrial cancer, are excluded, unless all of the following conditions are met: stage not greater than I-B; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell or other International Federation of Gynecology and Obstetrics (FIGO) grade 3 lesions Patients with uncontrolled infection Patients with concurrent severe medical problems unrelated to the malignancy that would significantly limit full compliance with the study or expose the patient to extreme risk or decreased life expectancy Patients with >= grade 2 peripheral neuropathy Patients with a history of allergic reactions to carboplatin and/or paclitaxel or chemically similar compounds; patients with allergic (hypersensitivity) reactions to these chemotherapeutic agents are NOT excluded IF they were successfully retreated following a desensitization program or protocol This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies Patients of childbearing potential, not practicing adequate contraception, patients who are pregnant or patients who are nursing are not eligible for this trial; to date, no fetal studies in animal or humans have been performed; the possibility of harm to a fetus is likely; bevacizumab specifically inhibits VEGF, which is responsible for the formation of new blood vessels during development, and antibodies can cross the placenta; therefore, bevacizumab should not be administered to pregnant women; in addition, there are unknown immediate and long-term consequences of chemotherapy administration to these women; in addition, surgical exploration as mandated by randomization during pregnancy may cause imminent mortal consequences; further, it is not known whether bevacizumab is excreted in human milk; because many drugs are excreted in human milk, bevacizumab should not be administered to nursing women; subjects will be apprised of the large potential risk to a developing fetus Patients with other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of the other cancer present within the last 5 years or whose previous cancer treatment contraindicates this protocol therapy This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients with active bleeding or pathologic conditions that carry high risk of bleeding such as a known bleeding disorder, coagulopathy, or tumor involving major vessels This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients with a history or evidence upon physical examination of central nervous system (CNS) disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases or a history of stroke within 5 years of the first date of treatment on this study This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients with clinically significant cardiovascular disease; this includes: Patients with significant cardiac conduction abnormalities, i.e. PR interval > 0.24 seconds (sec) or 2nd or 3rd degree atrioventricular (AV) block Uncontrolled hypertension, defined as systolic > 150 mm Hg or diastolic > 90 mm Hg Myocardial infarction, cardiac arrhythmia or unstable angina < 6 months prior to registration New York Heart Association (NYHA) grade II or greater congestive heart failure Serious cardiac arrhythmia requiring medication Grade II or greater peripheral vascular disease (exception: episodes of ischemia < 24 hours [hrs] in duration, that are managed non-surgically and without permanent deficit) History of cerebrovascular attack (CVA) within six months This criterion applies only to the patients enrolled before August 29, 2011 and those enrolled after this date electing to receive bevacizumab; patients who have had a major surgical procedure, open biopsy, dental extractions or other dental surgery/procedure that results in an open wound, or significant traumatic injury within 28 days prior to the first date of treatment on this study, or anticipation of need for major surgical procedure during the course of the study; patients with placement of vascular access device or core biopsy within 7 days prior to the first date of treatment on this study Patients undergoing pre-treatment secondary cytoreduction will undergo therapy with bevacizumab on cycle #2 Patients undergoing pre-treatment surgery for purposes other than cytoreduction may also participate provided they meet eligibility; patients randomized to arms containing bevacizumab must wait a minimum of 28 days since that procedure to begin protocol treatment; patients who undergo an uncomplicated port placement must wait a minimum of 7 days to begin protocol treatment

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (paclitaxel, docetaxel, carboplatin)<br>Patients receive paclitaxel IV over 3 hours or docetaxel IV over 1 hour and carboplatin over 30 minutes on day 1. Treatment repeats every 21 days. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm II (paclitaxel, docetaxel, carboplatin, bevacizumab)<br>Patients receive chemotherapy as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Docetaxel<br>* Given IV<br>* Other names: Taxotere Injection Concentrate;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Paclitaxel<br>* Given IV<br>* Other names: Taxol Konzentrat;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm III (gemcitabine hydrochloride, carboplatin)<br>Patients receive gemcitabine hydrochloride IV over 60 minutes on days 1 and 8 and carboplatin as in Arm I. | Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|
| Experimental: Arm IV (gemcitabine hydrochloride, bevacizumab, carboplatin)<br>Patients receive gemcitabine hydrochloride IV as in Arm III, bevacizumab IV and carboplatin IV as in Arm II. | Biological: Bevacizumab<br>* Given IV<br>* Other names: rhuMab-VEGF;Drug: Carboplatin<br>* Given IV<br>* Other names: Ribocarbo;Drug: Gemcitabine Hydrochloride<br>* Given IV<br>* Other names: LY188011;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine if Surgical Secondary Cytoreduction in Addition to Adjuvant Chemotherapy Increases the Duration of Overall Survival in Patients With Recurrent Platinum Sensitive Epithelial Ovarian Cancer, Peritoneal Primary or Fallopian Tube Cancer | The treatment regimens will be compared with a logrank procedure which includes all of the patients categorized by their randomly assigned treatment. The logrank test will be stratified by the secondary surgical debulking status (randomized to undergo cytoreduction, vs randomized to not undergo secondary cytoreduction vs not a candidate or did not consent to secondary surgical cytoreduction) and the duration of treatment free-interval prior to enrolling onto this study (6-12 months vs > 12 months). The median duration of follow-up is calculated by the reverse Kaplan-Meier method. | The time frame is 82.5 months (median duration of follow-up) | 
| To Determine if the Addition of Bevacizumab Increases the Duration of Overall Survival Relative to Second-line Paclitaxel and Carboplatin Alone in Patients With Recurrent Platinum Sensitive Epithelial Ovarian, Peritoneal Primary or Fallopian Tube Cancer | The treatment regimens will be compared with a logrank procedure which includes all of the patients categorized by their randomly assigned treatment. The logrank test will be stratified by the secondary surgical debulking status (randomized to undergo cytoreduction, vs randomized to not undergo secondary cytoreduction vs not a candidate or did not consent to secondary surgical cytoreduction) and the duration of treatment free-interval prior to enrolling onto this study (6-12 months vs > 12 months). The median duration of follow-up is calculated by the reverse Kaplan-Meier method. | The time frame is 82.5 months (median duration of follow-up). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (Chemotherapy Analysis) | Progression-free survival was defined as the time from randomization to cancer progression as shown on radiography, according to the RECIST version 1.0 criteria, an increase in the CA125 level according to Gynecologic Cancer InterGroup (GCIG) criteria, global deterioration of health, or death from any cause. | Radiographic assessment of disease was conducted during chemotherapy and then every 6 months during the maintenance / surveillance phase | 
| Progression Free Survival (Surgery Analysis) | Progression-free survival was defined as the time from randomization to cancer progression as shown on radiography, according to the RECIST version 1.0 criteria, an increase in the CA125 level according to Gynecologic Cancer InterGroup (GCIG) criteria, global deterioration of health, or death from any cause. | Radiographic assessment of disease (in patients with measurable and non-measurable disease) was conducted Every three months for two years and then every 6 months after completion of chemotherapy during the maintenance/surveillance phase. | 
| Summary of Adverse Events (CTCAE Version 4.0) | Number of treated patients with at least one adverse event reported (assessed by Common Terminology Criteria for Adverse Events (version 4.0)) | During treatment period and up to 100 days after stopping the study treatment, a median duration of 82.5 months | 
| Patient Reported Quality of Life (Chemotherapy Analysis) | Patient reported quality of life was measured with the Treatment Outcome Index (TOI) of the Functional Assessment of Cancer Therapy for ovarian cancer (FACT-O TOI). The FACT-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). Each item in the FACT-O TOI was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). The FACT-O TOI score ranges 0-100 with a large score suggests better QOL. | 1. Prior to cycle 1 (baseline), 2. Prior to cycle 3 (6 weeks post cycle 1), 3. Prior to cycle 6 (15 weeks post cycle 1), 4. 6 months post cycle 1, 5. 12 months post cycle 1. | 
| Patient Reported Physical Function (Chemotherapy Analysis) | Patient reported physical functioning was measured with physical functioning subscale of the RAND SF-36. The Physical Functioning Subscale consists of 10 items concerning activities of daily living: walking, climbing stairs, bathing, dressing, and performance of physical activities. Each item is rated on a three-point scale of limitation of activity due to the patients' health from 1=limited a lot to 3=not limited. The total PF score is the summation of item scores and then rescaled to 0-100. A larger score suggests better physical functioning. | 1. Prior to cycle 1 (baseline), 2. Prior to cycle 3 (6 weeks post cycle 1), 3. Prior to cycle 6 (15 weeks post cycle 1), 4. 6 months post cycle 1, 5. 12 months post cycle 1. | 
| Patient Reported Quality of Life (Surgery Analysis) | Patient reported quality of life was measured with the Treatment Outcome Index (TOI) of the Functional Assessment of Cancer Therapy for ovarian cancer (FACT-O TOI). The FACT-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). Each item in the FACT-O TOI was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). The FACT-O TOI score ranges 0-100 with a large score suggests better QOL. | 1. Prior to surgery, 2. 6 weeks post-surgery, 3. 15 weeks post-surgery, 4. 6 months post-surgery, 5. 12 months post-surgery. | 
| Patient Reported Physical Functioning (Surgery Analysis) | Patient reported physical functioning was measured with physical functioning subscale of the RAND SF-36. The Physical Functioning subscale consists of 10 items concerning activities of daily living: walking, climbing stairs, bathing, dressing, and performance of physical activities. Each item is rated on a three-point scale of limitation of activity due to the patients' health from 1=limited a lot to 3=not limited. The total PF score is the summation of item scores and then rescaled to 0-100. A larger score suggests better physical functioning. This measure was completed by US patients only. | 1. Prior to surgery (baseline), 2. 6 weeks post-surgery, 3. 15 weeks post-surgery 4. 6 months post-surgery, 5. 12 months post-surgery |