An Adjuvant Cytotoxic Chemotherapy from Japan

Back in 1992 researchers in Japan reported provocative results using adjuvant cytotoxic chemotherapy for node negative RCC [Masuda 1992], but the study has major limitations.

The Treatment

The treatment uses three cytotoxic chemo drugs:

• Vinblastine: This drug has had the reputation of being one of the most effective cytotoxic drugs against RCC, but that still means a response rate in the 10% range with few or no lasting responses. It is an approved drug, though not specifically for RCC.
  
  
• Adriamycin: This is a potent and classic cytotoxic which is approved everywhere though again not specifically for RCC. RCC (excepting some variants such as sarcomatoid) isn't known to respond to Adriamycin as far as I know. This drug causes hair loss and other side effects classically associated with "chemo". It can also cause cumulative damage to the heart though not normally at the low dose used here.
  
  
• UFT: This oral cytotoxic is a modification of the standard drug 5-fluorouricil (also known as 5-FU) is said to make it more potent. 5-FU which is an IV drug that has been used in combination with immunotherapy in RCC but isn't effective in RCC by itself. The authors do cite two Japanese studies showing UFT can cause response in RCC. UFT is not an approved drug in the United States, but it is approved in Europe and Japan (and possibly elsewhere).

The treatment consisted of an IV infusion of Vinblastine and Adriamycin every 4 weeks for a total of five infusions. UFT was given orally for 2 to 3 years. The doses of Adriamycin and Vinblastine were relatively low.

Side effects were mainly hair loss and mild to moderate appetite loss, presumably just during the IV chemo part of the protocol.

The Good News

• Amazing Survival: Survival at both 3 and 5 years was 96%, compared to the historical controls at 72% and 60%. Moreover, the one death was also the only patient who had a recurrence. Although the patients had a favorable prognosis as a group, this is still extraordinary.
  
  
• Good Follow-Up Duration: All patients had at least 30 months follow-up time, and the follow-up time averaged 50 months. This is long enough to get a good idea of long term survival, since most relapses happen in the first few years.

The Caveats

• Historical Control: This wasn't a randomized trial, but instead used a historical control, meaning that the survival of the treated patients is compared to a "similar" group of patients treated earlier. Historical controls are considered much less reliable than randomized controls. They also apparently made no effort to match the control patients to treated patients for stage or grade, though the percentages were still similar in each group.
  
  
• Small Size: Only 31 patients were treated, which increases the chance of a spurious or at least vastly exaggerated result just due to chance alone.
  
  
• Cytotoxic Chemotherapy: RCC is notoriously resistant to cytotoxic chemotherapy. No cytotoxic chemotherapy has ever given better than transient response in metastatic RCC and response rates are dismal. Given the depth and completeness of cytotoxic chemotherapy's failure for advanced RCC it would be truly remarkable for the same treatment to be highly effective as adjuvant therapy. It seems improbable.
  
  
• Not Replicated: As far as I know there has been no attempt to replicate these results or to test them in a randomized trial. Nothing would bolster this more than an independent replication. I haven't seen any suggestion of interest in this treatment outside this one paper.
  
  
• Favorable Prognosis Patients: Patients tended to be low stage and low grade (also they used an unspecified and unconventional 1-3 grading system - the standard Fuhrman Nuclear Grade is a 1-4 scale). Anyway, nearly half of their patients were stage I and only 19% stage III. Likewise, all of the treated patients were grade 1 or 2 (on their scale) with no grade 3. Despite this, their patients still had unusual survival.
  
  

Bottom Line, I think despite the promising results from this small study, given this treatment is somewhat toxic and that the results seem improbable given the body of evidence on cytotoxic drugs and RCC, there just isn't enough evidence to recommend it, but it's really too bad this has never been investigated further.

(Acknowledgement: Thanks to Mike Fischer, who has supported and funded CancerGuide, for pointing out this interesting research out to me.)

Reference

Masuda F, Nakada J, Kondo I, Furuta N.

Adjuvant chemotherapy with vinblastine, adriamycin, and UFT for renal-cell carcinoma.

Cancer Chemother Pharmacol. 1992 ;30(6):477-9. [PubMed Abstract (will open in new window)]