PROTOCOLLO CA OVAIO

APPENDIX: TABLES AND FIGURES
Table 1: Effect of salvage therapies as a function of first-line platinum response

Therapy Reference No. of Patients Response rate (%) Median survival (months)
Resistant Sensitive
Paclitaxel Trimble et al. [47] 1000 22 - 8.8
Carboplatin+ ifosfamide Lorusso et al.[59] 35 0 56 -
Ifosfamide Sutton et al. [64] 41 20
Markman et al. [65] 41 12
Hexamethylmelamine Vergote et al.[63] 61 14 - 9*
Tamoxifen Hatch et al. [66] 105 18
5-FU + leucovorin Look et al. [58] 49 6.6 17.2 -
Etoposide Rose et al. [67] 41 26.8 10.8
41 34.1 16.5
Lipossomal Doxorubicin Muggia et al. [68] 35 25.7 11
Gemcitabine Friedlander et al. [69] 38 13.9 6.7
Lund et al. [70] 42 19 6.2
Topotecan Huinink et al.[62] 112 13.3 28.8 15
Bookman et al. [71] 139 12.4 19.2 11
High-dose Chemotherapy Stiff et al. [61] 100 81 94 13
Intraperitoneal Chemotherapy** Piver et al.[72] 63 7 50 29
Markman et al. [60] 89 11 56 -
*Responders; **Cisplatin-Based Regimen
 Table 2: Survival after secondary cytoreduction at second-look operation
Author/year Before SLO After-SLO Survival Measure P-value
Tumour size No RD No
Podratz et al., 1988 [79] Microscopic <0.5cm >0.5cm 26 62 28 55% 21% 14% 4 year <0.01
Lippman et al., 1988 [80] <2cm >2cm 14 13 42% 0% 4 year 0.001
Heintz et al., 1988 [81] Negative Microscopic 0-1.5cm 16 9 27 55% 53% 20% 5 year 0.03
Hainsworth et al., 1988 [82] Microscopic Macroscopic 10 16 28 mos 22 mos Median NS
Hoskins et al., 1989 [83] Microscopic Macroscopic 17 50 → → Microscopic Microscopic Macroscopic 17 16 33 62%  (a) 51%  (b) <10%  (c) 5 year (a) x (b): NS (a)+(b)  x (c): 0.013
Bertelsen, 1990 [84] Macroscopic 94 <1cm >1cm 35 59 25% 4% 4 year 0.001
Podczaski et al., 1990 [85] <2cm >2cm 19 19 31% 6% 5 year <0.01
Potter et al., 1992 [86] Microscopic Macroscopic 20 36 56% <10% 5 year <0.05
Hempling et al., 1997 [87] Microscopic Macroscopic 35 28 → → Microscopic Microscopic Macroscopic 35 18 10 39.8  (a) 20  (b) 5-y (a) x (b): NS
Williams et al., 1997 [88] Microscopic <1cm >1cm 29 55 69 → → → Microscopic Microscopic <1cm Microscopic <1cm >1cm 29 21 34 15 18 36 26 mos 23 mos 14 mos 23 mos 14 mos 8 mos RR(CI95%) 1.0 0.7 (0.4, 1.35) 1.5 (0.86, 2.66) 1.3 (0.68, 2.68) 1.5 (0.76, 2.97) 3.1 (1.66, 5.67) 0.15 <<0.01 0.25
Gadducci et al., 2000 [89] Microscopic Macroscopic <2cm >2cm 11 11 43 mos  (a) 19.5 mos  (b) 24 mos  (c) 10 mos  (d) Median (a) x (b): 0.002 (c) x (d): 0.0001
Raspagliesi et al., 1999 [90] 28 40 1cm > 1cm* 27% 3% 4-y 0.04
Obermaier & Sevelda, 2001 [91] Microscopic <2cm >2cm 22.9 mos 17.8 mos 15.5 mos Median NS
No; number of patients; RD: residual disease; SLO: second look operation; mo:; months; NS: not significant; *At the surgical exploration; RR: relative risk of death with respect to microscopic initial tumour size; CI: confidence interval.

Table 3: Pharmacokinetic profile of some chemotherapies when delivered intraperitoneally associated with hyperthermia
Drug AUCpe/AUCpl Tumour penetration Mechanism of hyperthermic modulation References
Doxorubicin 87.9 4-6 cell layers Enhanced tissue absorption; increased Dx aglycon concentration 152,153
Gemcitabine 12.5 -26.8 NA Enhanced tissue absorption; activation to triphosphate metabolite; inhibition of DNA damage repair 155,156
Mitomycin C 23.5 NA Enhanced tissue absorption; cell membrane permeability alteration; increased activation and intracellular alkilation, inhibition of DNA damage repair 162
Mitoxantrone 5.6 - 15.2 5-6 cell layers yes 130,109
Cisplatin 14 2-2.5 mm Enhanced tissue absorption; increased DNA adduct formation; increased activity at low pH; Increased production of O2 radicals; reduction of  cisplatin resistance 111,140,141,142,143
Carboplatin 1.9 - 5.2 0.2-0.5 mm Enhanced tissue absorption; increased DNA adduct formation; 129,111,149
Oxaliplatin 16 1-2 mm Enhanced tissue absorption 157,158
Paclitaxel 1000* NA Increased disruption of microtubules system and apoptosis 159,160,161
Dx: Doxorubicin; NA: data not available in the current literature; * under normothermic condition; AUC, area under the concentration-time curve in peritoneal cavity (AUCpe) and plasma (AUCpl). The AUC is calculated integrating the concentration curve over time and reflects the total amount of drug present in peritoneal cavity of plasma.

Table 4: Response rate of intraperitoneal chemotherapy in ovarian cancer according to the drug
Drug Dose (mg/m2) Number of patients Response (%) Reference
CR PR
5-FU 845 - 1170 14 0 7 162
Methotrexate 30 5 0 50 163
Doxorubicin 10 - 50 10 0 30 153
Mitoxantrone 14* 8 0 50 130
Cisplatin 90 - 270 18 0 55 145
60 - 150 27 33 146
50 23 65 144
120 - 180 4 25 50 147
Cisplatin + Doxorubicin* 28
Carboplatin 200 - 650 27 15 148
200 - 500 22 18 36 149
150 - 350 22 14 9 150
Paclitaxel 60** 76 24 160
* under hyperthermic condition; **weekly for 16 weeks
Table 5: Ovarian epithelial cancer histologic classifications (WHO) · Serous cystadenocarcinomas · Mucinous cystadenocarcinomas · Endometrioid adenocarcinomas · Clear cell cystadenocarcinomas · Unclassified tumors that cannot be allotted to one of the above groups no histology · Other malignant tumors (malignant tumors other than those of the common epithelial types are not to be included with the categories listed above)
 Table 6 – WHO Toxicity grading criteria
Grade 1 2 3 4
HEMATOLOGICAL
Hemoglobin (g/dl) 9.5 - 10.9 8.0 - 9.4 6.5 - 7.9 < 6.5
WBC / mm3 4000 - 3000 2999 - 2000 1999 - 1000 < 1000
Platelets (1000) 75 - 99 50 -74 25 - 49 < 25
Hemorrhage Petecchiae Mild blood loss Gross blood loss Debilitating blood loss
GASTROINTESTINAL
Bilirubin (mg/dl) 1.9 - 3.7 3.8 - 7.5 7.5 - 15.0 > 15.0
Oral Soreness / erythema erythema, ulcers, can eat solid Ulcers requires liquid diet only Alimentation not possible
Nausea/Vomiting nausea Transient vomiting Vomiting requiring therapy Intractable vomiting
Diarrhea Transient < 2 days Tolerable, but > 2 days Intolerable, requiring therapy Hemorrhagic, dehydration
RENAL
Creatinine (mg/dl) 2.1 - 4.0 4.1 - 8.0 8.1 - 16.0 > 16.0
Peripheral edema Mild Severe Symptomatic nerve or vascular compression Tissue ischemia
Hematuria Microscopic Gross Gross+(coaguli) Obstructive
Perfusion 20 - 35 ml/h 10 - 20 ml/h 5 - 10 ml/h £ 5 ml/h
PULMONARY Mild symptoms Exertional dyspnea Dyspnea at rest intubation required Complete bed rest
CHILLS --- Mild Requiring and responsive to medication Unresponsive to medication
ALLERGIC Edema Bronchospasm; no parenteral therapy required Bronchospasm; parenteral therapy Anaphylactic
CUTANEOUS Erythema Dry desquamation, vesiculation, prurit Moist desquamation, ulceration pruritis requiring medication Exfoliative dermatite necrosis requiring surgical intervention
INFECTION Minor infection Moderate infection Severe systemic infections Requires surgical removal and drainage
CARDIOVASCULAR
Rhythm Sinus tachycardia, >110 at rest Unifocal PVC artrial arrhythmia Multifocal PVC Ventricular tachycardia
Hypotension --- Responds to fluids Requires and responds to pressors Unresponsive to pressors
Ischemia --- --- Angina or ischemia changes in EXG Myocaridal infection
NEUROTOXICITY
State of communication Transient lethargy Sonnolence < 50% of waking hours Sonnolence > 50% f waking hours Coma
Orientation intellect Oriented but with mild confusion Mild disorientation, but able to care for self Disorientation requiring help with activities of daily living Grossly disoriented
ABDOMINAL PAIN Mild Moderate Moderate/severe Very severe
CATHETER STATUS Minor infection or leakage Moderate infection Removal required due to severe pain or severe infection Skin loss, severe infection

Table 7: Evaluation of treatment response
Type of response Description
Clinical response
Complete response (cCR): 100% disappearance of all objectives signs of cancer, by clinical, Ca 125 and radiologic criteria, for minimum period of 1 month.
Partial response (cPR) Tumour regression >50% in the product of the two perpendicular diameters of main measurable lesions and the absence of appearance of new lesions or tumour progression elsewhere, for a minimum period of 1 month.
Stable disease (cSD) <25% increase and <50% regression in the product of the two perpendicular diameters of main measurable lesions
Disease progression (cDP) >25% increase in the product of the two perpendicular diameters of main measurable lesions (despite the simultaneous regression of other lesions) or appearance of new lesions elsewhere

Table 8: Treatment related morbidity and mortality classification
Grade I No complications
Grade II Minor complications
Grade III Major complications (requiring reoperation or ICU admission or interventional radiology
Grade IV In hospital mortality

Table 9: Performance status score
ECGO (or Subrod) scale [106] Karnofsky score (%)
0 Asymptomatic and fully active 100
1 Asymptomatic; fully ambulatory; restricted in physically strenuous activity 80 - 90
2 Symptomatic; ambulatory; capable of self care; more than 50% of waking hours are spent out of bed 60 - 70
3 Symptomatic; limited self-care; spends more than 50% of waking hours in bed, but not bedridden 40 - 50
4 Completely disabled; no self-care; bedridden 20 - 30

Table 10: Preoperative abdominopelvic CT scan criteria for optimal cytoreduction
Attachment of omentum to spleen
Disease > 2cm in one of following sites:
· Mesentery
· Liver surface of parenchyma
· Diaphragm
· Gallbladder fossa
· Suprarenal paraaortic nodes
· Pericardiac nodes
· Pulmonary or pleural nodules


Figure 1: Flowchart of eligible patients
 

1 Patients deemed non-optimally cytoreducible by Nelson et al criteria [46] will be excluded to the Random 2 Patients with early relapse after completion of primary systemic therapy (<6 months) LRT = Loco regional therapy; APCT: abdominopelvic CT scan; IPHP: intraperitoneal hyperthermic perfusion.
 Figure 2: Peritoneal Cancer Index The index will be calculated as the sum of the lesion size of the tumour in all the abdominopelvic regions involved by locally recurrent sarcoma and by sarcomatosis. The score of the peritoneal Cancer Index ranged from 1 to 39 and will be calculated for each patients.
Figure 3: Diagram of completeness of cytoreduction according to the diameter of largest residual disease [168]

15. Abbreviations

APCT: Abdominopelvic computed tomography scan
ARSC Advisory review subcommittee
AUCpe Area under curve in the peritoneal cavity
AUCpl Area under curve in the plasma
BSA Body surface area
cc-0/1/2/3 Completeness of cytoreduction according to Sugarbaker’s criteria
cCR Clinical complete response
CDDP Cisplatinum
cDP Clinical disease progression
CI Confidence interval
cPR Clinical partial response
CRS Cytoreductive surgery
cSD Clinical stable disease
Dx Doxorubicin
ESC Executive subcommittee
IPHP Intraperitoneal hyperthermic perfusion
LRT Locoregional therapy
MMC Mitomicyn C
mos months
No Number of patients
NS Not significant
PCI Peritoneal cancer index
RD Residual disease
RDPC Randomisation and Data processing committee
RR Relative Risk
SEC Scientific and Ethical committee
SLO Second look operation
TEMC Treatment effect monitoring committee
TNF a Tumour necrosis factor a

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