Appropriateness of systemic treatments in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

Table 1 Variables used to construct clinical patient scenarios in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

Variable	Range of values
Anatomic site	Pancreatic neuroendocrine tumors
Line of treatment	Observation; first-line treatment; second-line treatment; third-line treatment
Patient’s primary problem	Uncontrolled secretory symptoms; uncontrolled tumor-related symptoms; rapid radiographic progression; nonrapid radiographic progression; no symptoms and no radiographic progression; no symptoms
Postmarker and postscan testing status	No progression from prior marker and scan; progression after prior marker and scan
Frequency of testing a patient with markers and scans	Every 3 mo; every 6 mo; every 9 mo; every 12 mo
Cytoreductive surgery	Optimal cytoreductive surgery; suboptimal cytoreductive surgery; not a candidate for surgery
Systemic therapy	Somatostatin analog; everolimus; sunitinib; cytotoxic chemotherapy; interferon-α; temozolomide-containing regimen; streptozotocin-containing regimen
Response to lower octreotide LAR dose	Previously responded to a lower dose or frequency; previously did not respond to a lower dose or frequency
Octreotide LAR frequency	Every 2 wk; every 3 wk; every 4 wk
Octreotide LAR dosing	30 mg; 40 mg; 60 mg; 90 mg; 120 mg

Table 2 Number of indications scored as ”inappropriate”, ”uncertain”, ”appropriate”, or as ”disagreement” in unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

	First Round Results				Second Round Results
Agreement	Frequency	Percent	CumulativeFrequency	CumulativePercent	Frequency	Percent	CumulativeFrequency	CumulativePercent
Inappropriate	73	37.1	73	37.1	94	46.5	94	46.5
Uncertain	39	19.8	112	56.9	44	21.8	138	68.3
Appropriate	59	29.9	171	86.8	62	30.7	200	99.0
Disagreement	26	13.2	197	100.0	2	1.0	202	100.0

Table 3 Average panel median rating and absolute deviation for clinical scenarios in patients with unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

Variable	First round results					Second round results
	Number of Scenarios	Mean	SD	Minimum	Maximum	Number of Scenarios	Mean	SD	Minimum	Maximum
Median	197	4.3	2.6	1.0	9.0	202	4.1	2.9	1	9.0
Absolute deviation	197	1.6	0.5	0.1	2.7	202	0.8	0.6	0	2.2

Table 4 Observation in patients with unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

Rate the appropriateness of observation without regional or medical therapy	In a patient whose primary problem is:
	Uncontrolled secretory symptoms	Uncontrolled tumor-related symptoms	Rapid radiographic progression	Nonrapid radiographic progression	No symptoms and no radiographic progression
	1.01 (0.0)	1.01 (0.0)	1.01 (0.0)	4.32 (1.2)	8.03 (1.3)

The medians of ratings represents the type of panel consensus that was reached for the particular patient scenario (cell).

¹Median rating 1-3 and no disagreement⁴ = “inappropriate”;

²Median rating 4-6 and no disagreement⁴ = “uncertain”; and

³Median rating 7-9 and no disagreement⁴ = “appropriate”; ⁴ > 2 responses in the range 1-3 and > 2 responses in the range 7-9 = “disagreement”.

Table 5 Observation in patients with unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

Rate the appropriateness of the frequency of testing in an asymptomatic patientWho has had	Markers and scans
	Every 3 mo	Every 6 mo	Every 9 mo	Every 12 mo
A. No progression from prior marker and scan	7.03 (1.5)	6.53 (1.8)	5.02 (1.5)	3.52 (1.7)
B. Progression after prior marker and scan	9.03 (0.2)	6.53 (1.6)	2.01 (1.0)	1.01 (0.5)

The medians of ratings represents the type of panel consensus that was reached for the particular patient scenario (cell):

¹Median rating 1-3 and no disagreement⁴ = “inappropriate”;

²Median rating 4-6 and no disagreement⁴ = “uncertain”; and

³Median rating 7-9 and no disagreement⁴ = “appropriate”; ⁴ > 2 responses in the range 1-3 and > 2 responses in the range 7-9 = “disagreement”.

Table 6 First-Line treatment in patients with unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

Rate the appropriateness of the following initial treatment options		In a patient whose primary problem is:
		Uncontrolled secretory symptoms	Uncontrolled tumor-related symptoms	No symptoms
No systemic therapy	Following optimal cytoreductive surgery	1.01 (0.0)	1.01 (0.0)	8.53 (1.5)
Somatostatin analogue		9.03 (0.0)	7.03 (1.1)	5.02 (0.7)
Everolimus		7.03 (0.5)	7.03 (0.9)	1.01 (0.4)
Sunitinib		7.03 (0.7)	7.03 (0.9)	1.01 (0.3)
Cytotoxic chemotherapy		5.02 (1.2)	7.54 (2.2)	1.01 (0.2)
No systemic therapy	Who had suboptimal cytoreductive surgery	1.01 (0.0)	1.01 (0.0)	5.02 (1.2)
Somatostatin analogue		9.03 (0.0)	6.02 (1.7)	5.02 (0.3)
Everolimus		7.03 (0.4)	7.03 (0.6)	5.02 (1.1)
Sunitinib		7.03 (0.5)	7.03 (0.5)	5.02 (1.2)
Cytotoxic chemotherapy		7.03 (1.0)	7.03 (0.9)	2.01 (1.2)
No systemic therapy	Who is not a candidate for surgery	1.01 (0.0)	1.01 (0.0)	5.02 (0.3)
Somatostatin analogue		9.03 (0.0)	5.02 (1.5)	6.53 (1.2)
Everolimus		7.03 (0.6)	8.03 (0.6)	5.02 (1.1)
Sunitinib		7.03 (0.8)	8.03 (0.4)	5.02 (1.2)
Cytotoxic chemotherapy		6.53 (1.1)	9.03 (0.8)	5.02 (1.5)

The medians of ratings represents the type of panel consensus that was reached for the particular patient scenario (cell):

¹Median rating 1-3 and no disagreement⁴ = “inappropriate”;

²Median rating 4-6 and no disagreement⁴ = “uncertain”; and

³Median rating 7-9 and no disagreement⁴ = “appropriate”; ⁴ > 2 responses in the range 1-3 and > 2 responses in the range 7-9 = “disagreement”.

Table 7 Second-line treatment in patients with unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

Rate the appropriateness of the following as a second-line medical treatment in a patient who has had an initial adequate trial of a somatostatin analogue	In a patient whose primary problem is:
	Uncontrolled secretory symptoms	Uncontrolled tumor-related symptoms	Rapid radiographic progression	Nonrapid radiographic progression	No symptoms and no radiographic progression
Higher dose/frequency of somatostatin analogue (e.g., > 30 mg dose or < 4 wk dosing of octreotide LAR)	9.03 (0.2)	3.01 (0.8)	2.01 (0.8)	5.02 (1.4)	1.01 (1.0)
Everolimus	8.03 (0.4)	9.03 (0.4)	8.03 (0.5)	8.03 (0.6)	1.51 (1.1)
Sunitinib	8.03 (0.7)	8.53 (0.8)	7.53 (0.7)	7.03 (0.7)	1.51 (1.0)
Cytotoxic chemotherapy	7.03 (0.8)	8.53 (0.8)	7.53 (1.4)	6.02 (1.0)	1.01 (0.8)
Interferon	5.02 (1.1)	4.02 (0.9)	4.02 (1.3)	3.52 (1.7)	1.01 (0.3)

The medians of ratings represents the type of panel consensus that was reached for the particular patient scenario (cell):

¹Median rating 1-3 and no disagreement⁴ = “inappropriate”;

²Median rating 4-6 and no disagreement⁴ = “uncertain”; and

³Median rating 7-9 and no disagreement⁴ = “appropriate”; ⁴ > 2 responses in the range 1-3 and > 2 responses in the range 7-9 = “disagreement”.

Table 8 Second-line treatment in patients with unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

Rate the appropriateness of increasing the dose or frequency of octreotide lar beyond 30 mg every 4 wk		Every 4 wk				Every 3 wk					Every 2 wk
In a patient whose primary problem is:		40 mg	60 mg	90 mg	120 mg	30 mg	40 mg	60 mg	90 mg	120 mg	30 mg	40 mg	60 mg	90 mg	120 mg
Uncontrolled secretory symptoms	Who previously responded to a lower dose or frequency	9.03 (0.7)	7.03 (0.7)	1.01 (0.5)	1.01 (0.3)	8.03 (0.8)	7.03 (0.6)	5.52 (1.5)	1.01 (0.6)	1.01 (0.4)	5.02 (2.0)	4.52 (2.2)	3.01 (1.9)	1.01 (0.1)	1.01 (0.1)
Uncontrolled tumor-related symptoms		6.02 (1.7)	5.02 (1.8)	1.01 (0.4)	1.01 (0.3)	5.52 (2.0)	4.52 (1.9)	3.52 (1.8)	1.01 (0.5)	1.01 (0.4)	1.01 (1.5)	1.01 (1.4)	1.01 (0.6)	1.01 (0.1)	1.01 (0.1)
Radiographic progression		5.02 (1.1)	4.52 (1.6)	1.01 (0.3)	1.01 (0.3)	5.04 (2.2)	4.02 (1.9)	2.51 (1.8)	1.01 (0.5)	1.01 (0.5)	1.01 (1.7)	1.01 (1.6)	1.01 (0.5)	1.01 (0.1)	1.01 (0.1)
Uncontrolled secretory symptoms	Who previously did not respond to a lower dose or frequency	7.03 (0.9)	7.03 (0.9)	1.01 (0.5)	1.01 (0.3)	6.02 (1.1)	6.02 (0.9)	3.52 (1.6)	1.01 (0.4)	1.01 (0.5)	3.01 (2.0)	2.51 (1.6)	2.01 (0.8)	1.01 (0.1)	1.01 (0.1)
Uncontrolled tumor-related symptoms		3.52 (1.4)	3.01 (1.5)	1.01 (0.3)	1.01 (0.2)	2.51 (1.0)	3.01 (1.0)	1.51 (0.5)	1.01 (0.2)	1.01 (0.2)	1.01 (0.7)	1.01 (0.4)	1.01 (0.3)	1.01 (0.1)	1.01 (0.1)
Radiographic progression		3.01 (1.4)	3.01 (1.5)	1.01 (0.2)	1.01 (0.2)	2.01 (0.7)	2.51 (1.1)	1.01 (0.6)	1.01 (0.3)	1.01 (0.3)	1.01 (0.6)	1.01 (0.4)	1.01 (0.2)	1.01 (0.1)	1.01 (0.1)

The medians of ratings represents the type of panel consensus that was reached for the particular patient scenario (cell):

¹Median rating 1-3 and no disagreement⁴ = “inappropriate”;

²Median rating 4-6 and no disagreement⁴ = “uncertain”; and

³Median rating 7-9 and no disagreement⁴ = “appropriate”; ⁴ > 2 responses in the range 1-3 and > 2 responses in the range 7-9 = “disagreement”.

Table 9 Third-line treatment in patients with unresectable metastatic well-differentiated pancreatic neuroendocrine tumors

Rate the appropriateness of the following as a third-line medical treatment in a patient who has had an adequate trial of two agents, one of which was a somatostatin analogue. Assume for each question that the agent being rated was not previously used	In a patient whose primary problem is:
	Uncontrolled secretory symptoms	Uncontrolled tumor-related symptoms	Rapid radiographic progression	Nonrapid radiographic progression	No symptoms and no radiographic progression
Higher dose/frequency of somatostatin analogue (e.g., > 30 mg dose or < 4 wk dosing of octreotide LAR)	9.03 (0.4)	3.01 (1.6)	2.51 (1.0)	4.52 (1.8)	1.01 (0.4)
Everolimus	9.03 (0.7)	9.03 (0.7)	8.03 (0.8)	7.03 (0.6)	1.01 (0.7)
Sunitinib	8.53 (0.7)	9.03 (0.7)	8.03 (0.8)	7.03 (0.7)	1.01 (0.7)
Interferon	5.02 (0.9)	4.52 (1.3)	4.02 (1.0)	3.01 (1.7)	1.01 (0.4)
Temozolomide-containing regimen	7.53 (1.4)	7.53 (1.2)	7.53 (1.5)	5.02 (1.3)	1.01 (0.6)
Streptozotocin-containing regimen	5.52 (1.3)	7.03 (1.4)	6.53 (1.2)	4.52 (1.6)	1.01 (0.4)
Cytotoxic Chemotherapy	6.53 (1.3)	8.03 (1.1)	8.03 (1.2)	5.52 (1.5)	1.01 (0.9)

The medians of ratings represents the type of panel consensus that was reached for the particular patient scenario (cell):

¹Median rating 1-3 and no disagreement⁴ = “inappropriate”;

²Median rating 4-6 and no disagreement⁴ = “uncertain”; and

³Median rating 7-9 and no disagreement⁴ = “appropriate”; ⁴ > 2 responses in the range 1-3 and > 2 responses in the range 7-9 = “disagreement”.