Preoperative or Perioperative Docetaxel, Oxaliplatin, and Capecitabine (GASTRODOC Regimen) in Patients with Locally-Advanced Resectable Gastric Cancer: A Randomized Phase-II Trial

Docetaxel associated with oxaliplatin and 5-fluorouracil (FLOT) has been reported as the best perioperative treatment for gastric cancer. However, there is still some debate about the most appropriate number and timing of chemotherapy cycles. In this randomized multicenter phase II study, patients with resectable gastric cancer were staged through laparoscopy and peritoneal lavage cytology, and randomly assigned (1:1) to either four cycles of neoadjuvant chemotherapy (arm A) or two preoperative + two postoperative cycles of docetaxel, oxaliplatin, and capecitabine (DOC) chemotherapy (arm B). The primary endpoint was to assess the percentage of patients receiving all the planned preoperative or perioperative chemotherapeutic cycles. Ninety-one patients were enrolled between September 2010 and August 2016. The treatment was well tolerated in both arms. Thirty-three (71.7%) and 24 (53.3%) patients completed the planned cycles in arms A and B, respectively (p = 0.066), reporting an odds ratio for early interruption of treatment of 0.45 (95% confidence interval (CI): 0.18–1.07). Resection was curative in 39 (88.6%) arm A patients and 35 (83.3%) arm B patients. Five-year progression-free survival (PFS) was 51.2% (95% CI: 34.2–65.8) in arm A and 40.3% (95% CI: 28.9–55.2) in arm B (p = 0.300). Five-year survival was 58.5% (95% CI: 41.3–72.2) and 53.9% (95% CI: 35.5–69.3) (p = 0.883) in arms A and B, respectively. The planned treatment was more frequently completed and was more active, albeit not significantly, in the neoadjuvant arm than in the perioperative group.

. Dose reduction for hematological toxicity (capecitabine). The daily dose of capecitabine is reduced by 25% at the first occurrence of grade-3 toxicity or the second occurrence of grade-2 toxicity. The daily dose is reduced by 50% at the first occurrence of grade-4 toxicity, the second occurrence of grade-3 toxicity and the third occurrence of grade-2 toxicity. Capecitabine is discontinued at the second occurrence of grade 4 toxicity.

Grades of Toxicity
Action to Be Taken during Toxicity Dose Reduction for the Next Cycle Preventive growth factors (G-CSF or GM-CSF) are not recommended. Their use may be considered in cases of prolonged or complicated severe neutropenia.

Non hematological toxicities
The dose modification grid for drug medications is as follows:

Hepatic toxicity
Liver function tests will be carried out before each planned treatment.  Capecitabine is controindicated if creatinine clearance is < 29 mL/min, while capecitabine can be reduced by 25% if creatinine clearance is 30-50 mL/min. If renal criteria for treatment are not met on day 1 of the chemotherapy cycle, re-evaluate weekly. If renal criteria for treatment are not met after 2 weeks, patients should go off treatment. Table S6. Dose reduction for neurologic toxicity.

Grade of neurologic toxicity at the time of planned treatment Docetaxel and oxaliplatin doses to be admnistered
Delay oxaliplatin and docetaxel treatment doses by 1 week, if grade ≥ 2 persists for > 2 weeks patient should go off study. If patient recovers to grade 1 toxicity, then dose of both drugs is reduced by 20%. If there is no recovery to grade 1 in two weeks, discontinue treatment.

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Patient is discontinued from the study If neurologic toxicity is grade > 1 at the time of the planned treatment, treatment is not administered. The patient is tested and monitored weekly. If toxicity has not resolved to grade ≤ 1 after two weeks, the patient must go off treatment.

Diarrhea and stomatitis and hand-foot sindrome.
Capecitabine administration will be interrupted if patient develops grade ≥ 2 diarrhea, stomatitis or hand-foot sindrome, and will be resumed after resolution to grade ≤ 1. Subsequent treatment cycles will be given at the appropriate dose adjustment (table S7). If toxicity reappears or recovery is not complete after a 2-week delay despite these reductions, treatment will be interrupted.

Anaphylactic reactions
Docetaxel can induce an anaphylactic reaction. It will therefore be helpful to administer steroids and antihistamines before each docetaxel infusion in patients who experience this reaction. Description and suggested management of docetaxel hypersensitivity reaction is as follows: Table S8. Management of anaphylactic reaction.
Mild symptoms: localized cutaneous reaction such as mild pruritus, flushing, rash

• consider decreasing the rate of infusion until recovery of symptoms, stay in bed, then, complete docetaxel infusion at the initial planned rate
Moderate symptoms: any symptom not listed above (mild symptoms) or below (severe symptoms), such as generalized pruritus, flushing, rash, dyspnea, hypotension with systolic blood pressure (BP) > 80 mm Hg • If severe reaction recurs despite additional premedication, the patient will go off treatment

Anaphylaxis (NCI Grade 4 reaction) • no further treatment
Management of Subsequent Treatment Cycles: The recommended pretreatment for subsequent infusions is clorfenamina 10 mg IV and 10 mg dexamethasone IV 60 minutes prior to docetaxel infusion. This is in addition to the prescribed oral dexamethasone.
Patients with hypersensitivity reactions to docetaxel are at risk of recurrent reactions. For patients who experience moderate or severe hypersensitivity reactions, docetaxel should be administered over a period of 2 hours for subsequent treatment courses in addition to premedication as outlined above.
These patients must be informed of the potential risk of recurrent allergic reactions and carefully monitored.
If the initial reaction is grade 4 according to NCI Common Toxicity Criteria for Allergy, the patient will receive no further treatment and will go off treatment. If a second severe reaction (grade 3) occurs despite additional premedications as outlined above, the patient will go off treatment. In the event of late hypersensitivity symptoms, e.g. appearance of localized or generalized pruritus within 1 week of treatment, symptomatic treatment may be given (e.g. oral antihistamine). Additional oral or IV premedication with antihistamine may also be given for the next cycle of treatment depending on the intensity of the reaction observed. No dose reduction will be made for any patient.

Fluid Retention
No docetaxel dose reduction is planned for fluid retention syndrome. For the purpose of toxicity evaluation, "fluid retention" is defined as the development of trace edema or cytologically negative pleural effusion, ascites, or pericardial effusion, and is graded as "mild", "moderate" or "severe" according to the definitions in the table below. Investigators should report the highest grade of edema or effusion. Table 9. Fluid retention grading criteria (docetaxel). Symptomatic, Intervention urgently required Patients developing new onset or symptomatic edema, or other signs of increasing fluid retention, should be treated with oral diuretics. Regimens which have been found to be effective in the management of fluid retention due to docetaxel are listed below. Diuretic therapy may be initiated in the order listed at the investigator's discretion: Spironolactone 50 mg daily up to TID.

EDEMA SEVERITY GRADING ACTION
Furosemide 40 mg PO daily if not responsive to spironolactone. Potassium supplements may be given as needed.
If, after a trial of 2 weeks the treatment is ineffective, treat with furosemide 20 mg PO daily plus metolazone 2.5 mg PO daily with potassium supplementation as needed.
Further therapy should be personalized, depending on the clinical situation. The clinical tolerance of the patients, the overall tumour response and the medical judgment of the investigator will determine if it is in the patient's best interest to continue or discontinue treatment.
If severe fluid retention is not responsive to symptomatic therapy, the patient should go off treatment.

Other Toxicities Not Specified Above
In case of toxicities ≤ grade 2, manage symptomatically if possible and resume treatment without dose reduction.
In case of toxicities ≥ grade 3, the drug suspected to be responsible for the toxicity should be delayed (for a maximum of 2 weeks) until resolution to ≤ grade 1 and then reduced by 20%. In case of no recovery within 2 weeks' delay or recurrence of the same toxicity, treatment should be interrupted.
No further dose increases are allowed. Alopecia (any grade) is excluded from these recommendations.
In case of unstable angor related to 5-FU administration, or myocardial infarction, treatment will be stopped.

Management of specific toxicities related to Capecitabine
Expected adverse effects of treatment: delayed diarrhea.

Delayed diarrhea
Treatment with Capecitabine may induce delayed diarrhea. No prophylactic agent will be given; in particular, loperamide will not be prescribed for prophylaxis. Patients will be advised to stop any laxative treatment they are taking and to avoid food and beverages that could accelerate intestinal transit.

Curative treatment
As soon as the first liquid stool or abnormal bowel movement occurs, the patient must immediately start loperamide, 2 capsules p.o., then 1 capsule p.o. every 2 hours for at least 12 hours and up to 12 hours of the last liquid stool, without exceeding a total treatment duration of 48 hours. Oral rehydration with large volumes of water and electrolytes will be prescribed during the whole episode.
If diarrhea persists for longer than 48 hours despite the recommended loperamide treatment, a 7-day oral prophylactic broad-spectrum antibiotic therapy with fluoroquinolone will be started after medical advice. The patient may require hospitalization for parenteral support. Loperamide will be replaced by another antidiarrheal treatment (e.g. octreotide).

Oral fluoroquinolone should be given to patients with:
-any grade-4 diarrhea; -grade-3 diarrhea plus neutropenia, or in the event of fever. Patients who experience concomitant vomiting or fever, or those with a performance status > 2, should be hospitalized immediately for rehydration.