Long-Term Efficacy of High-Activity ¹¹¹In-Pentetreotide Therapy in Patients with Disseminated Neuroendocrine Tumors

MATERIALS AND METHODS

RESULTS

Seventy-six treatments with high-activity ¹¹¹In-octreotide therapy were given over 3 y (Table 1). In 3 patients (2 with carcinoid tumor, 1 with a malignant histiocytoma), there was a significant reduction in the tumor mass classifiable as a partial response by 6 mo after the last therapy (Table 2). In an additional 2 patients, there was a complete response at 6 mo with no anatomically or scintigraphically visible tumor seen (Fig. 1). Both of these patients had medullary cell carcinoma of the thyroid. In 1 patient, the serum calcitonin fell from 48 mmol/L to an undetectable level and in the other patient it fell from 39 mmol/L to an undetectable level. A further 7 patients attained stability (i.e., no change in the size of a previously growing tumor) at 6 mo after the last treatment. There was further tumor progression in the remaining 4 patients, 3 of whom died within the initial 6-mo assessment period.

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FIGURE 1.

Patient with MCT shows disease extent in neck and chest and abdomen (arrows) before treatment (A) and complete response 9 mo later after 3 treatments with high-activity ¹¹¹In-pentetreotide (B). Note colonic uptake is physiologic.

Efficacy

At the initial assessment, 6 mo after the last treatment, 5 patients (30%) had progressive disease (Fig. 2). These patients included 3 with carcinoid tumors and 2 with nonsecreting tumors but with bone metastases: 1 with gastrinoma and 1 with fibrolamellar tumor and cardiac secondary tumors. At 12 mo after the final treatment, 9 patients showed disease progression (56%); the additional 4 patients included 3 with carcinoids (2 of whom had or developed bone metastases) and the 4th patient had a glucagonoma. By 18 mo after the last therapy, 11 patients (69%) had disease progression. The 2 new patients with progressive disease included a patient with a carcinoid and the patient with malignant histiocytoma (who was the only patient with an initial response who had disease progression by 18 mo). The mean progression-free survival was 12 mo, although the median was lower at 9 mo. For those 11 patients who survived 6 mo beyond their last treatment, the mean progression-free survival was 15.75 mo, with a median of 16 mo.

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FIGURE 2.

Disease-free survival curves for 18 mo after last treatment with high-activity ¹¹¹In-pentetreotide. Censored denotes last data point plotted by SPSS.

Of the patients without evidence of disease progression at 18 mo, 2 patients had medullary cell carcinoma of the thyroid and 3 patients had carcinoid tumors, but with disease mainly limited to the liver.

Mortality

At 6 mo, there were 3 deaths, 1 of which was not related to cancer (Fig. 3). At 12 mo, there was 1 additional cancer death. At 18 mo, there were 3 additional deaths (1 was a cancer death but from small cell lung cancer and not from the patient’s carcinoid). Therefore, there was a total mortality of 7 of 16 patients (44%) at 18 mo after the last treatment. The mean time interval between disease progression and death was 5 mo, with 6 of these patients dying within 6 mo of the disease progression.

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FIGURE 3.

Survival curves for 18 mo after last treatment with high-activity ¹¹¹In-pentetreotide. Censored denotes last data point plotted by SPSS.

DISCUSSION

Previous studies performed by our group and others have shown that high-activity ¹¹¹In-pentetreotide can show antitumor activity (13,15). In this series of patients, 31% had an objective response from the treatment of their disease with high-activity ¹¹¹In-pentetreotide. A further 44% had a period of tumor stability, with no growth in tumor size for at least 6 mo after the end of treatment. Therefore, at least 75% of patients showed some benefit from the treatment. This finding compares well with the results of de Jong et al. (16), where 14 of 21 patients (67%) showed either stability or a response. However, a higher proportion of their patients showed partial or complete response (43%). This finding probably reflects that, on average, their patients received twice the activity of ¹¹¹In-pentetreotide (5–7 GBq for each administration) that our patients received. The number of nonresponders in both groups is almost identical (25% for our group and 33% for the group of de Jong et al.). However, the profile of the patients treated in terms of tumor type and degree of progression may be very different in different studies, making comparison difficult. In addition, one needs to take into account the nonhomogeneous nature of the tumors, so that not all cells have an equal uptake of ¹¹¹In-pentetreotide.

It is possible that increasing activities of ¹¹¹In-pentetreotide convert more of the responders from stability to tumor shrinkage. Unfortunately, de Jong et al. (16) do not indicate how long the stability or the tumor regression they reported was maintained.

The response of the tumor may be related to tumor burden so that any given amount of radiation will be spread among more tumor if there is a large tumor bulk, thus reducing the amount of radiation per gram of tumor. This may explain why the 2 patients with MCT had a good tumor response, because they both had a low tumor load compared with some of the carcinoid patients. This may also explain why the patients with MCT did well in our group compared with those treated by de Jong et al. (15,16). In the Dutch group, the patients with MCT all had widespread disease with significant tumor mass. To treat larger tumor masses it may be important to use an isotope that emits a β-particle that can pass through several cells, resulting in a path of ionization across these cells and increasing tumor kill. This could be one of the reasons why good tumor reduction has been reported in some patients with bulky tumors treated with ⁹⁰Y-labeled somatostatin (17).

The results of our group were achieved with no toxicity, which was not the experience from a similar study performed in the United States. In this American study, 2 treatments of 4–6 GBq were given 4–6 wk apart (12). This resulted in 4 patients having some toxicity; 2 had grade 3 hematologic toxicity needing supportive therapy. Most of our patients received a lower activity (about 3–4 GBq), but had more treatments, which would result in a more fractionated dose of radiation to the marrow and kidneys, a technique often used to reduce morbidity from radiation therapies (18). However, it is also clear that the dosimetric assessment of the agents may not be accurate because it would be expected that, in patients receiving therapeutic activities of ¹¹¹In-pentetreotide, the radiation dose to the kidneys would be above the level at which toxicity would be expected (19). This does not appear to the case with these patients or those series reported by our group and others (12,13,16).

The treatment was remarkably well tolerated by all of the patients, although 2 had some shaking and abdominal cramps; this was probably related to of the base octreotide given and, despite the low dose (30 μg), there was some pharmacologic action though this was self-limiting. Interestingly, this finding was not related to previous exposure because 1 patient had previous somatostatin analog therapy and 1 had not. This low level of side effects, compared with those expected from radiolabeled antibodies, probably occurs because they are less allergenic, containing no product of animal origin, and the fact that much smaller amounts of product are given—for example, in antibody therapy, anything from a milligram to a gram of antibody may be used. However, the response rate using high-activity ¹¹¹In-pentetreotide appears to be better than that seen with therapeutic radiolabeled antibodies in solid tumors (20).

There remains the question of whether the natural history of progression of the patient’s disease has been altered. This is difficult to answer from our study, alone, because it is a phase II study without the use of a control, no-treatment arm. It may be possible to look at historical controls but the problem is that the patient mix may be different. Most studies look at all patients with NETs in all stages of the disease or those who are still eligible for surgery where the 5-y survival may be as high as 53% (21). However, the patients treated by ¹¹¹In-pentetreotide tend to be those who have been refused a surgical option, normally because of more advanced disease. The closest population to that included in our study that can be used for comparison is the group of patients in the above study who did not have surgery and in whom 67% survived 1 y but only 34% survived 3 y. However, until one can identify a good control group, it is difficult to determine that treatment with ¹¹¹In-pentetreotide changes the natural history of disease.

CONCLUSION

This study has helped to establish the principle that radiotargeted therapy with peptides can be effective in stopping tumor progression in some patients. ¹¹¹In-Pentetreotide is safe to give and is well tolerated. There can be a sustained response for many months after treatment and this can be achieved with minimal or no toxicity. The best results were seen in those patients with less tumor burden.